Biological Reviews - 2019 - Jinesh - The Genetic Script of Metastasis

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Biol. Rev. (2020), 95, pp. 244–266. 244
doi: 10.1111/brv.12562
The genetic script of metastasis

Goodwin G. Jinesh1,2∗ and Andrew S. Brohl2,3∗
1
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, U.S.A.
2
Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, U.S.A.
3
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, U.S.A.
ABSTRACT
Metastasis is a pivotal event that changes the course of cancers from benign and treatable to malignant and difficult to
treat, resulting in the demise of patients. Understanding the genetic control of metastasis is thus crucial to develop efficient
and sustainable targeted therapies. Here we discuss the alterations in epigenetic mechanisms, transcription, chromosomal
instability, chromosome imprinting, non-coding RNAs, coding RNAs, mutant RNAs, enhancers, G-quadruplexes, and
copy number variation to dissect the genetic control of metastasis. We conclude that the genetic control of metastasis
is predominantly executed through epithelial to mesenchymal transition and evasion of cell death. We discuss how
genetic regulatory mechanisms can be harnessed for therapeutic purposes to achieve sustainable control over cancer
metastasis.
Key words: lnc-RNA, miRNA, ce-RNA, linc-RNA, imprinting, methylation, H3K27ac/acetylation, metastasis.
CONTENTS
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
II. Epigenetics of metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
III. Emergency transcription, translation, neutrophil extracellular traps and metastasis . . . . . . . . . . . . . . . . . . . . . . 247
IV. Positive and negative regulation of metastasis by coding gene transcription . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
V. Metastasis: the good, bad and ugly transcripts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
VI. Non-coding RNAs and super-regulation of metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
VII. Metastasis: the missing, super-expressed and imprinted transcripts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
VIII. Harnessing genetic control over metastasis for therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
IX. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
X. Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
XI. Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
XII. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
I. INTRODUCTION tumorigenesis and metastasis share many properties in

common such as cellular transformation (Li et al., 2007),
Cancers begin with the growth of abnormal cells which metastatic cells display unique characteristics that enable
either continue to grow at the same primary site as primary them to thrive in new microenvironments that are often rich
tumors by uncontrolled proliferation or remain dormant in immune cell populations (such as liver, lung, bone marrow,
for variable durations without successful relocation from lymph nodes, etc.). Often cancer cells tune immune cells as
the primary site. However, over time, the primary tumor promoters of metastasis (Kitamura, Qian & Pollard, 2015).
cells acquire metastasis capabilities, i.e. to migrate and settle At the genetic level, metastasis is driven by cancer stem cells
in various parts of the body often with a preference toward that display augmented genomic instability (Jinesh & Kamat,
particular organs. Metastasis is the key event that changes the 2017b; Bakhoum et al., 2018; Seton-Rogers, 2018), at the
prognosis of patients toward poor survival and is the major metabolic level they display efficient glycolysis (Zhang et al.,
cause of cancer-related death (Spano et al., 2012). Although 2017a), at the immune level they evade phagocytosis and are
* Authors for correspondence (Tel: +1 8137452187; E-mail: goodwinjinesh@gmail.com); (Tel: +1 8137453242; E-mail:
andrew.brohl@moffitt.org)
Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

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Coding and non-coding RNAs regulating metastasis 245
capable of inducing local anergy (Chen et al., 2014), and at II. EPIGENETICS OF METASTASIS
a cellular level they are able efficiently to evade cell death
(Jinesh & Kamat, 2017b). Most of these special characteristics In multiple human cancer types and metastasis, the
of metastatic cells are encoded by genetic information (mostly production of coding and non-coding RNAs is largely
oncogenic) or are regulated by loss of inhibitory genetic controlled by DNA methyltransferases (DNMTs) (DNMT-1,
control elements (tumor-suppressor mechanisms). However, -3A, -3L), chromatin acetylation changes by activation or
the pivotal events that are controlled by genetic regulatory inactivation of transcription factors and repressors, histone
mechanisms are not clear and a more detailed understanding methylation erasers (enhancer of zeste 2 polycomb repressive
of the genetic aspects of metastasis is required to confront complex 2 subunit: EZH2) and DNA demethylation agents
metastasis. (Tet methylcytosine dioxygenases: TET-1, -2, and -3)
Transcription conveys genetic information from genomic (Chatterjee, Rodger & Eccles, 2018) and the removal of DNA
DNA to RNA level and is an important step that reg- secondary structures such as G-quadruplexes and R-loops
ulates metastasis. For example, mediator of RNA poly- by helicases (Drosopoulos, Kosiyatrakul & Schildkraut, 2015)
merase II transcription subunit 19 (Med19), a co-activator or their stabilization by G-quadruplex binding factors (Saha
of transcription of nearly all RNA polymerase II et al., 2017) (Fig. 1A, B). Thus the epigenetic changes involved
(RNA-Pol-II) target genes, promotes metastasis (Yu et al., in metastasis are complex and are tightly regulated (Fig. 1).
2014). Post-transcriptional stability of RNAs also regu- Methylation is primarily localized to CpG islands
lates metastasis. For example, trans-activation responsive that are predominantly associated with enhancers and
RNA-binding protein-2 (TARBP2), a double-stranded RNA promoters, where CpG island hypermethylation prevents
(dsRNA) binding protein, binds to a family of GC-rich enhancer or promoter activation (Engel et al., 2004). A
structural cis-regulatory RNA-related elements also called change in CpG island hypermethylation to hypomethylation
TARBP2-binding structural elements (TBSEs) to destabi- usually enables the activation of enhancers which is
lize the TBSE-containing messenger RNAs (mRNAs) to associated with histone-3 lysine-27 acetylation (H3K27ac)
promote metastasis (Goodarzi et al., 2014; Lokody, 2014). (Fagnocchi, Poli & Zippo, 2018) (Fig. 1). Tumor-suppressor
Furthermore, it is emerging that a huge body of regula- genes are usually hypermethylated at CpG islands in
tory RNAs [long non-coding RNAs (lncRNAs), microRNAs tumors, but a large-scale hypomethylation shift takes
(miRNAs), competing endogenous RNAs (ceRNAs), etc.] place at oncogenes during metastasis and possibly during
affect RNA stability to regulate metastasis (see Section VI). tumorigenesis (Fagnocchi et al., 2018). For example, in
Genome-wide alterations in repression of genes are also pancreatic ductal adenocarcinoma, metastasis is driven by
associated with metastasis. For example, polycomb repres- forkhead box A1 (FOXA1)-driven large-scale enhancer
sive complex-2 (PRC-2) represses a large panel of genes activation (Roe et al., 2017). Receptor tyrosine kinases
during metastasis (Yu et al., 2012). However, the genetic (RTKs) and therapeutic measures activate a wide variety
composition of metastatic tumors can vary among cancer of enhancers through Ras/mitogen activated protein kinase
types and often between patients who have the same can- (MAPK) signaling to drive metastasis (Su et al., 2012; Nabet
cer type. Few candidate genes have emerged as drivers of et al., 2015). A number of genes are differentially methylated
metastasis across multiple cancer types. For example, loss or in metastasis with the number of hypomethylated genes
mutation of tumor-suppressor transcripts such as p53 have nearly doubled in metastatic colorectal cancers compared
emerged as a prominent mechanism for metastasis, as a with primary tumors (Vidal et al., 2017). By contrast, CpG
majority of metastatic cancers harbor defects in p53 expres- island methylation in metastasis is similar to that in primary
sion or function (Powell, Piwnica-Worms & Piwnica-Worms, prostate cancers (Yegnasubramanian et al., 2004), suggesting
2014; Zehir et al., 2017). that the methylation status of tumor suppressors relative to
Research on the genetic regulation of metastasis is oncogenes could contribute to differences in CpG island
expanding rapidly. Thus there is a pressing need to methylation in a cancer-type-dependent manner. In breast
unify the core genetic regulatory mechanisms that govern cancer, a strong CpG island methylator phenotype is linked
metastasis to streamline metastasis and drug discovery to metastasis (Fang et al., 2011) possibly via the repression
research. Herein, we discuss how metastasis is regulated at of tumor/metastasis-suppressing genes. Hypomethylation
the epigenetic and transcriptional levels and explain how can also be associated with metastasis: metastatic colon
mutations and other alterations in mRNA transcripts or at cancer cells exhibit the lowest degree of methylation at gene
chromosomes deregulate control over metastasis. We also regulatory regions (Rokavec, Horst & Hermeking, 2017).
discuss how different types of non-coding RNAs (ncRNAs) Thus, in the context of metastasis, both hypermethylation
exert a super-regulatory role over critical mRNA transcripts and hypomethylation can positively or negatively regulate
to enable or to suppress metastasis. The emerging literature metastasis depending on the target genes and tissue types
shows that the genetic control of metastasis is tightly linked involved (Fig. 1A).
to reversible epithelial-to-mesenchymal transition and In addition to methylation, complex DNA
evasion of cell death. Finally we explain how RNA/genetic three-dimensional structures can hamper or promote
therapeutics might help to regain sustainable control over expression of genes within chromosomes. The best
metastasis or even have the potential to cure cancer. known examples are euchromatin and heterochromatin

246 Goodwin G. Jinesh and Andrew S. Brohl
Fig. 1. Broad genetic factors regulating metastasis. (A) Left, genome-wide chromatin changes differ between primary and metastatic
cancer cells. Centre, methylation and acetylation drives local chromatin state, shown here at the nucleosome level. Right, formation
of G-quadruplex (G4) in single-stranded DNA (ssDNA) and its removal by a DNA helicase. (B) A single lattice of G-quadruplex
formed by guanines of the same or different DNA strand(s). The potassium ion at the centre can promote stabilization of
the G-quadruplex. (C) Regulation of gene transcription. Upper gene shows how the CpG island, DNA methylation, repressor
complex and G-quadruplex can repress transcription of a gene. Lower gene shows how histone acetylation and assembly of the
transcription complex enables transcription after removal of the G-quadruplex by helicase. CpG, CG-rich DNA connected by
phosphodiester bonds; DNMT, DNA methyl transferase; G4, G-quadruplex; HAT, histone acetyltransferase; H3K27ac, histone-3
lysine-27 acetylation; KDM, lysine demethylase; LOCK, large organized chromatin K9(lysine-9) modification; Me, methylation;
PRC-2, polycomb repressive complex-2; TET, Tet methylcytosine dioxygenase; TF, transcription factor; TGF-β, transforming
growth factor-β.
zones within chromosomes. PRC-1 and PRC-2 are form secondary structures that stall the progression of
involved in large-scale chromatin compaction to form transcription (Kwok & Merrick, 2017). The best example
heterochromatin and histone-3 lysine 27 methylation is G-quadruplex formation (Fig. 1A) where the ssDNA
(H3K27me3), which results in the repression of large blocks forms non-covalent Hoogsteen-like hydrogen bonding
of genomic regions (Margueron & Reinberg, 2011). Loss between guanines (Tian et al., 2018) of same-strand or
of PRC-2-dependent H3K27me3 activates HIF-2α-driven adjacent ssDNA (Kwok & Merrick, 2017) (Fig. 1B). Like
C-X-C motif chemokine receptor 4 (CXCR4) to promote methylation events, G-quadruplex formation can influence
metastasis in clear-cell renal cell carcinomas (Vanharanta metastasis depending on whether it forms in oncogenes or in
et al., 2013). Chromatin higher order structures are usually tumor-suppressor genes (see Section 4). Unlike methylation
relaxed as foci within the genome by differential binding events that primarily target DNA, G-quadruplexes influence
of factors like CCCTC-binding factor (CTCF), structural both DNA and RNA (see Sections III & IV). Human
maintenance of chromosomes (SMC), and RAD21 cohesin telomerase reverse transcriptase (TERT) is a major player
complex component (RAD21), which creates access for in metastasis (Hannen & Bartsch, 2018) and its expression
transcription factors or demethylation agents to open is tightly blocked by G-quadruplex structures that form at
up the chromatin for transcription. The transcription the promoter region, which provide a binding option for the
factors in turn recruit additional transcription machinery metastasis suppressor NME2/NM23. NM23 in turn allows
components by protein–protein interactions to the gene the RE1 silencing transcription factor (REST transcriptional
promoter and or to the enhancer regions. Transcription is repressor) to silence TERT transcription (Saha et al., 2017).
usually associated with DNA-strand separation by helicases, In addition to CpG methylation, non-CpG methylation
and single-stranded DNAs (ssDNAs) at these sites often also influences transcription. For example, REST is

involved in silencing non-CpG methylated genomic regions an intermediate step of metastasis by regulating multiple
(Zhang et al., 2017b) whereas the specificity protein 1 hallmarks of tumorigenesis and metastasis (Goodwin, Willis
(Sp1) transcription factor can activate transcription even & Kamat, 2014; Jinesh, Laing & Kamat, 2016a; Jinesh
when the chromatin is methylated (Holler et al., 1988). & Kamat, 2016b, 2017b; Jinesh et al., 2016b,c,d, 2018b;
Non-CpG methylation is known to be enriched in miRNA Jinesh, 2017; Stone, 2017). Transcription and translation of
clusters such as chromosome-19 miRNA cluster (C19MC) anti-apoptotic factors during the execution phase of apoptosis
(Jinesh, Flores & Brohl, 2018a). In contrast to H3K27me3, is essential to overcome cell death. Selective upregulation of
H3K9me2 in large organized chromatin H3K9-modified a subset of mRNAs is known to occur during apoptosis
(LOCK) heterochromatin is enriched in regional peritoneal and is distinct from gene expression patterns of necrosis
metastasis but is reduced in distant lung metastasis of (Sato et al., 2008). More importantly, the mRNA expression
pancreatic ductal adenocarcinoma (PDAC) (Alderton, 2017) pattern of a subset of genes is strikingly different in cells
(Fig. 1A). In addition to heterochromatin methylation that undergo definitive cell death, compared with cells that
differences, euchromatin also displays differences in survive after apoptosis using the blebbishield emergency
chromatin acetylation at K27 and methylation at K36 program (Jinesh & Kamat, 2017b). Therefore we coin the
(H3K27ac and H3K36me3) between local and distant terms ‘emergency transcription’ and ‘emergency translation’
metastasis of PDAC (Alderton, 2017). Very interestingly, for transcription or translation events that occur during the
these distant-metastasis-associated chromatin remodeling cell death process to promote cell death or cell survival,
changes were reversed by inhibition of the oxidative branch respectively (Figs 2B and 3). Emergency transcription and
of the pentose phosphate pathway (McDonald et al., 2017). translation can take place during apoptosis even when global
This raises the possibility that the carbohydrate metabolic mRNA synthesis is shut down [e.g. vascular endothelial
changes associated with distant metastasis could remodel growth factor-A (VEGF-A), p53 (Jinesh & Kamat, 2017b),
the chromatin state to favor metastasis-associated gene death activated protein kinase (DAPK), and p53 up-regulated
expression. modulator of apoptosis (PUMA) expression (Emerson &
In addition to large-scale genomic regulation, repression of Espinosa, 2006; Gomes et al., 2006)]. Activating transcription
individual genes also can play a role in metastasis (Table 1). factor-3 (ATF-3) which acts during apoptotic stress can
However, it should be noted that individual gene-expression promote p53 stability and downstream target transcription
changes could be part of large-scale epigenetic changes. to promote apoptosis (Yan & Boyd, 2006; Wang et al., 2017a).
For example, a set of differentially expressed interleukin-11 Similarly, the p30-Von Hippel–Lindau (VHL) isoform
(IL-11), connective tissue growth factor (CTGF), CXCR4, (which is known to stabilize p53 expression) is translated only
and matrix metallopeptidase 1 (MMP-1) genes regulate during the conditions that terminate blebbishield emergency
metastasis to bone (Kang et al., 2003) and another set of program-mediated survival of apoptotic cancer stem cells
differentially expressed genes that includes inhibitor of DNA (Jinesh & Kamat, 2017a). Wild-type TA-p53 (transactivation
binding 1 (Id1), MMP-1, C-X-C motif chemokine ligand 1 domain containing p53) can promote cell death to prevent
(CXCL1), prostaglandin-endoperoxide synthase 2 (PTGS2), metastasis by transcribing and activating downstream targets
vascular cell adhesion molecule 1 (VCAM1), and epiregulin such as BCL2-associated X (Bax) (Fischer, 2017), PUMA
(EREG) promote lung metastasis (Minn et al., 2005). Hence, (Nakano & Vousden, 2001) and NOXA (PMA-induced
it is likely that these sets of genes are part of large-scale protein) (Oda et al., 2000); all three gene products promote
epigenetic alterations and thus epigenetics plays a dominant mitochondrial apoptosis but often are already available
role in metastasis by remodeling the genomic landscape to as proteins at mitochondria. Regulator of chromosome
repress or to express a set of genes. Large-scale chromatin condensation-2 (RCC2), a non-canonical p53 target is
remodeling is usually associated with the DNA damage transcribed (using a palindromic binding site within RCC2
response or trans-differentiation of cells. In the context of promoter) in response to the apoptosis-inducing agent
metastasis, these two events are related to evasion of cell etoposide, which blocks Ras-related C3 Botulinum toxin
death and epithelial to mesenchymal transition (EMT). substrate 1 (Rac-1) activation and metastasis by impeding
migration (Song et al., 2017).
While p53 acts as a central node that promotes the
III. EMERGENCY TRANSCRIPTION, emergency transcription of death-related transcripts, its
TRANSLATION, NEUTROPHIL defects co-operate with Kirsten rat sarcoma viral oncogene
EXTRACELLULAR TRAPS AND METASTASIS homolog (K-Ras) and TERT to overcome cell death
(Fig. 2C). Ras like proto-oncogene-A (RalA) activation that
The blebbishield-emergency program is a process in which occurs during the blebbishield emergency program (Jinesh
apoptotic cancer stem cells overcome cell death signals & Kamat, 2016c) prevents p53 stabilization, and inhibition
by upregulating anti-apoptotic factors during the execution of Ral-GTPase is required to stabilize and reactivate p53
phase of apoptosis, to reconstruct themselves from apoptotic to inhibit malignant transformation (Tecleab, Zhang &
bodies and to undergo cellular/malignant transformation Sebti, 2014). Interestingly, apoptotic cancer stem cells
(Jinesh et al., 2013, 2018b; Jinesh & Kamat, 2016a,c, 2017b) block p53-mediated repression of Galectin-3 during the
(Fig. 2A). The blebbishield emergency program emerges as blebbishield emergency program which increases metastasis

Table 1. Coding genes/gene products that act as positive and negative regulators of metastasis through genetic mechanisms. Genes
are shown in italic type, their proteins in Roman type, and RNAs are underlined
Metastasis regulatory Type of metastasis

candidates regulation Genetic mechanism regulating metastasis
Med19 Positive Transcription of RNA-Pol-II target genes
TARBP2 Positive Destabilizes target RNAs containing TBSEs
TP53 Positive Mutations (codon-72), truncations, deletions and epigenetic silencing of
p53 promote metastasis through Galectin-3 expression
FOXA1 Positive Global enhancer activation
Ras/MAPK Positive Global enhancer activation
TERT Positive Overcomes replication limit by extending telomeric DNA
TERT -promoter Positive Mutation-introduced ETS binding site augments TERT transcription
PRC2 Positive Loss of PRC2-mediated H3K27me3 promotes metastasis through
HIF-2α/CXCR4 axis
Profilin-2 Positive Relieves Smad-2/3 from HDAC1-mediated repression to promote EMT
VEGF-A Positive G-quadruplex in VEGF-A mRNA promotes IRES translation during
emergencies to promote metastasis
NFE2L2/NRF2 Positive G-quadruplex in NRF2 mRNA promotes IRES translation to promote
metastasis during oxidative emergencies
SOX2 Positive EMT and blebbishield emergency program stimulate Sox-2 expression to
promote metastasis
CTCF Positive Regulates expression of EMT regulator SNAIL
HPOX Positive Regulates expression of EMT regulator SNAIL
Snai1-1 Positive Promotes EMT
HIF-1 Positive Promotes EMT and transcribes Fascin
STAT-3 Positive Promotes EMT while blocking TGF-β-driven apoptosis
hnRNPK Positive Transcribes MMP2
TWIST1 Positive Promotes EMT and transcribes complement C3
DNMT-1 and RelA/p65 Positive Repress metastasis suppressor gene BRMS-1
DNMT-1 Positive Promotes EMT
RICTOR Positive RICTOR mediates TGF-β-induced EMT and metastasis
PREP1 Positive Transcriptionally activates TGF-β-driven EMT and metastasis
HMGA2 Positive Mediates TGF-β-driven EMT and metastasis
KLF-8 Positive Transcribes CXCR4 to promote SDF-1-driven EMT
ETV-1 Positive Promotes SDF-1/CXCR4 axis of EMT
RUNX2 Positive Promotes EMT
Sp1 Positive Promotes VEGF-A transcription and blebbishield emergency program
Pea3 Positive Promotes EMT by transcribing MMPs
FoxQ1 Positive Required for TGF-β-driven EMT and metastasis
Pit-1 Positive Promotes EMT
IGF1R Positive Promotes Sp1 function to offer apoptosis resistance
YY1 Positive Promotes EMT through Snail and inhibits apoptosis by inactivating p53
N-Myc Positive Promotes NDRG2 transcription
KRAS Positive Mutations constitutively activate K-Ras to blunt death-receptor signaling
to promote metastasis
K-Ras Positive Promotes metastasis through blebbishield to immune cell
fusion-mediated CIMICS genomic instability
RRM2 Positive RRM2 fusion with c2orf48
SLC22A3 Positive A-to-I RNA editing impedes the expression of SLC22A3
c-MET Positive Regulates liver metastasis
CEACAM (multiple) Positive Loss of imprinting control unmasks CEACAMs to promote metastatic
adhesion at target organs
Zeb1 Positive Promotes EMT by repressing E-cadherin
p53-wild type Negative Promotes apoptosis in response to DNA damage or genomic instability
PRC2 Negative Co-operates with H3K27me3 to maintain heterochromatin status
MET Negative Point mutation (H1351N) blocks metastasis
Necdin Negative Suppresses c-Myc
Nkx2-1 Negative Represses the chromatin regulator HMGA2
SPDEF Negative Promotes epithelial phenotype
BRMS-1 Negative Promotes epithelial phenotype
YY-2 Negative Transcribes the metastasis negative regulatory gene AES
TIEG Negative Represses EGFR transcription
CDKN2A/p16INK4A Negative Silencing p16 transcription enables metastasis
TIP30 Negative Represses osteopontin transcription to suppress EMT

Table 1. Continued

candidates regulation Genetic mechanism regulating metastasis
HMGB-1 Negative Blocks CREB-dependent transcription
XRP44X Negative Blocks Elk3-dependent transcription
REST Negative Silences TERT through NME2/NM23-mediated binding at
G-quadruplex at the promoter region
MCC Negative Promotes E-cadherin-mediated inhibition of β-catenin to suppress lymph
node metastasis
BAX , PUMA, NOXA Negative Promote mitochondrial apoptosis in response to p53-dependent
transcription
RCC2 Negative Palindromic p53 binding site-dependent transcription results in blockade
of Rac-1 activation and metastasis
NME2/NM23/nm23-H2/ nm-23-β Negative Binds to G-quadruplex at TERT -promoter to prevent TERT
transcription. Also negatively regulates c-Myc/ gelatinase-A
transcription
TERT -promoter Negative G-quadruplex at TERT -promoter prevents TERT transcription
ARF Negative Inhibits the EMT and metastasis promoting transcription factor FOXM1
TA-TP63 Negative Dicer-dependent mechanism
A-to-I RNA editing, adenosine-to-inosine RNA editing; CIMICS, chromosomal instability with morphologically identical chromosome
sets; EMT, epithelial to mesenchymal transition; TBSE, TARBP2-binding structural elements.
by fusion of apoptotic cancer stem cells with immune The role of therapy-induced apoptosis in metastasis
cells (Jinesh & Kamat, 2017b). Notably, p53 expression can be ascertained by the induction of metastasis shortly
is masked in cells undergoing the blebbishield emergency after front-line therapies (Paez-Ribes et al., 2009; Ebos,
program to enable Galectin-3 expression (Jinesh & Kamat, 2015). Interestingly, neutrophils have the extraordinary
2017b). Ewing Sarcoma oncogene (EWSR1) is a VHL target ability to form extracellular DNA traps called neutrophil
upregulated during the blebbishield emergency program extracellular-DNA traps (NETs), which have been shown to
(Jinesh & Kamat, 2017a) and is known to undergo fusion promote metastasis. Production of NETs is an emergency
with multiple genes (Embree, Azuma & Hickstein, 2009; cell death program of neutrophils to tackle pathogens, but
Deng et al., 2011; Kujiraoka et al., 2017) to lead metastasis is misused by cancer cells to promote metastasis (Park et al.,
(Thway et al., 2013). 2016) (Fig. 2D). Histone hyper-citrullination drives NET
Emergency translation on the other hand, rapidly converts formation while preventing chromatin condensation (Wang
the mRNAs into proteins to tackle ongoing apoptosis. et al., 2009) and is co-driven by cathepsin-G and neutrophil
For example, cellular inhibitor of apoptosis protein-2 elastase (Papayannopoulos et al., 2010; Park et al., 2016). NET
(c-IAP2) gets translated during blebbishield emergency predominantly sequesters circulating tumor cells (CTCs)
program to inhibit death receptor signaling (Jinesh et al., to promote extravasation during metastasis (Cools-Lartigue
2016c). VEGF is a driver of the blebbishield emergency et al., 2013) (Fig. 2D). Thus evasion of cell death processes
program (Jinesh & Kamat, 2016c) that stimulates SRY-box-2 through emergency transcription and translation is one of
(Sox-2) to enable self-renewal and metastasis (Kim et al., the major routes to metastasis, and NETs play a role in
2017). G-quadruplexes impede cap-dependent translation metastasis.
but promote internal ribosome entry site (IRES)-dependent
translation of VEGF mRNA to drive metastasis (Kusters et al.,
2007; Morris et al., 2010; Cammas et al., 2015) (Fig. 2B). Once
the apoptotic cells reprogram their transcription, translation IV. POSITIVE AND NEGATIVE REGULATION OF
and ongoing apoptosis toward survival, blebbishields METASTASIS BY CODING GENE
form and fuse with immune cells to acquire migratory TRANSCRIPTION
and metastatic behavior through insulin-like growth
factor binding protein-5 (IGFBP5) (Jinesh & Kamat, Apart from emergency transcription, regular transcription
2017b) (Figs 2A and 3). Nuclear factor, erythroid-2-like-2 of protein-coding genes also powerfully regulates metastasis.
(NRF2) also exhibits G-quadruplex-dependent translation in The genetic regulation of metastasis by coding genes broadly
response to oxidative emergency and promotes metastasis falls under two major regulatory mechanisms: EMT and
(Wang et al., 2016; Lee et al., 2017). Thus emergency apoptosis resistance (Table 1, Fig. 3). Numerous studies link
transcription and translation during apoptosis can determine transcription to EMT and/or apoptosis resistance in the
the initiation or inhibition of metastasis, and G-quadruplexes context of metastasis. Cancer-associated fibroblasts (CAFs)
play a pivotal role in this context. promote lung metastasis through transforming growth

Fig. 2. Emergency transcription and translation in the context of the blebbishield emergency program and genetic changes
during neutrophil extracellular trap formation. (A) Commencement of apoptosis initiates the blebbishield emergency program
which reassembles apoptotic bodies to form blebbishields. Emergency translation and transcription can either promote survival or
promote cell death. Loss of surface E-cadherin and its reappearance at the protein level is shown (black arrows) to mark events
analogous to the classic epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), respectively.
(B) Regulation of emergency transcription by G-quadruplex (G4) and helicases: note that G4 can stall the transcription machinery
(top panels). Emergency translation is characterized by inhibition of cap-dependent translation by stalling ribosomes and promotion
of IRES translation (bottom panels). (C) Major mutations associated with cancer metastasis and their role in apoptosis evasion and
immortality. (D) Formation of neutrophil extracellular traps (NETs) by pathogens or circulating tumor cells (CTCs) help to anchor
CTCs to the luminal side of vascular endothelium to promote vascular exit of CTCs in the context of metastasis. Elastase and
cathepsin-G promote NET formation and the extruded DNA contains citrullinated core histones. c-Myc, avian myelocytomatosis
viral oncogene homolog; GoF, gain of function mutations; IRES, internal ribosome entry site; K-Ras, Kirsten rat sarcoma viral
oncogene homolog; TP53, tumor protein-53.
factor β1 (TGF-ß1)/Smad signaling to transcribe lncRNA repression to enable TGF-ß1 signaling to promote lung
HOTAIR (HOX transcript antisense RNA) to promote cancer metastasis (Tang et al., 2015). Galectin-3 is a
EMT by targeting cyclin-dependent kinase-5 (CDK5) by prominent metastasis regulator (Zhao et al., 2009; Chen
H3K27me3 (Ren et al., 2018) where histone remodeling et al., 2013) and the tumor suppressor p53 suppresses the
is done by PRC-2 (Gupta et al., 2010). Profilin-2 acts transcription of Galectin-3 in tumor cells by regulating
upstream to TGF-ß/Smad signaling by relieving Smad-2/3 the promoter element located within the second intron
from histone deacetylase-1 (HDAC1)-mediated epigenetic (Raimond et al., 1995; Jinesh & Kamat, 2017b). Galectin-3

Fig. 3. Genetic control of epithelial-to-mesenchymal transition (EMT) and apoptosis evasion, showing that both processes act in
parallel to execute metastasis. E-cadherin loss can be brought about by proteases or genetic means during apoptosis or EMT to
enable detachment from neighboring primary tumor cells. Emergency translation and transcription of ATF-3 can promote definite
cell death but VEGF-A can promote the blebbishield emergency program when accompanied by p53 defects and cIAP upregulation
and K-Ras activation. Immune cell fusion of the blebbishield promotes IGFBP5-mediated migration to enable distant metastasis. In
EMT, E-cadherin loss is largely controlled by genetic mechanisms to lose the epithelial state. When accompanied by extracellular
matrix (ECM) remodeling and matrixmetalloproteinase (MMP) activation, the mesenchymal cells migrate to enter the vascular
endothelium or reach the cerebrospinal fluid (CSF) through complement component C3. Neutrophil extracellular traps (NETs)
promote vascular exit near metastatic sites and the cells undergo mesenchymal-to-epithelial transition (MET) through enhanced
c-Myc transcription-dependent E-cadherin upregulation. *See Tables 1-3 for the genetic control RNAs involved. ATF-3, activating
transcription factor-3; cIAP, cellular inhibitor of apoptotic protein; c-Myc, avian myelocytomatosis viral oncogene homolog;
IGFBP5, insulin-like growth factor binding protein-5; K-Ras, Kirsten rat sarcoma viral oncogene homolog; TGF-β, transforming
growth factor-β; TWIST1, Twist basic helix–loop–helix transcription factor-1; VEGF-A, vascular endothelial growth factor-A.
is also regulated by CpG islands (Ahmed, Banerjee & Vasta, also regulates TGF-ß-induced EMT by binding to the
2007) indicating that the CpG-island-mediated repression promoter of Snail family transcriptional repressor (SNAIL)
of Galectin-3 might be lost during metastasis. Another (Bhattacharya, Hur & Dhasarathy, 2017). In addition to
prominent mechanism that suppresses tumorigenesis and CTCF, HOPX (homeodomain-only protein homeobox) also
metastasis is by repressing TERT transcription through regulates SNAIL to promote metastasis (Ren et al., 2017).
the metastasis suppressor NM23/NME2, which binds to SNAIL-1 stimulates osteosarcoma metastasis by blocking
G-quadruplex and brings the REST repressor to the TERT E-cadherin expression (Yang et al., 2014) and suppression of
promoter (Saha et al., 2017). Transcriptional silencing of the E-cadherin expression promotes metastasis through an EMT
MCC gene by promoter methylation in colorectal cancers and ß-catenin-dependent mechanism (Wu et al., 2012). HIF-1
(which unlock ß-catenin by reducing E-cadherin expression) promotes metastasis by transcribing fascin (Zhao et al., 2014)
is associated with lymph node metastasis (Benthani et al., and also induces EMT (Higgins et al., 2007). Leukotriene B4
2018). Sox-2, a stemness transcription factor required for receptor-2, metastasis associated-1 (MTA-1), Janus kinase-2
metastasis of lung cancer (Xiang et al., 2011), is a by-product (JAK-2) and IL-6 activate signal transducer and activator of
of EMT (Migita et al., 2017). The chromatin insulation transcription-3 (STAT-3) to promote metastasis (Seo, Park
factor CTCF controls the expression of metastasis-associated & Kim, 2012; Pakala et al., 2013; Lei et al., 2017) of which
genes such as CTBP1 (C-terminal binding protein-1), STAT-3 is a potent inducer of EMT (Rokavec et al., 2014).
SERPINE1 (Serpin family E member-1) and SRC to promote Transcription of EMT regulator MMP-2 by heterogeneous
metastasis of ovarian cancer cells (Zhao et al., 2017), and nuclear ribonucleoprotein K (hnRNPK) also promotes

metastasis (Zhu et al., 2017). A classic EMT regulator TWIST & Bonavida, 2017) through EMT and apoptosis resistance
is also tightly linked to metastasis (Kang & Massagué, by transcription of SNAIL (Palmer et al., 2009) and inhibition
2004). TWIST1 regulates transcription of complement of p53, respectively (Sui et al., 2004).
component C3 (Rupaimoole, Sood & Afshar-Kharghan, Similar to positive regulation of metastasis by promoting
2013) and C3 promotes leptomeningeal metastasis through EMT and survival of apoptotic cancer stem cells through the
cerebrospinal fluid (CSF) (Boire et al., 2017) (Fig. 3). Nuclear blebbishield emergency program, transcription of negative
factor-κB (NF-κB) subunit p65/RelA represses metastasis regulators of EMT and positive regulators of mitochondrial
suppressor gene BRMS-1 by recruiting DNMT-1 (Liu et al., apoptosis can also negatively regulate metastasis Table 1).
2012) a mechanism that can promote metastasis, where Metastasis suppressor NM23-H2 is one of the classic
DNMT-1 also can regulate EMT and metastasis (Lee et al., examples for the negative regulation of metastasis by
2016). Transcription of RICTOR (rapamycin-independent controlling c-Myc (v-Myc, avian myelocytomatosis viral
companion of mTOR complex 2) is also linked to metastasis oncogene homolog) transcription (Postel et al., 1993).
(Sun et al., 2016a). In non-small cell lung adenocarcinoma Another related metastasis suppressor NM23-ß functions by
PREP1 (Pbx regulating protein-1) transcription factor transcriptional repression of gelatinase-A by interfering with
induces EMT through the TGF-ß1/Smad-3 pathway to T-box protein-1 (YB-1) (Cheng et al., 2002). Intriguingly,
promote metastasis (Risolino et al., 2014). Similarly HMGA2 NM23 can induce the epithelial phenotype to prevent
(high mobility group AT-hook-2), which induces EMT invasiveness (Boissan et al., 2010). Similarly, necdin suppress
through TGF-ß, also drives metastasis (Morishita et al., c-Myc to suppress metastasis (Lee et al., 2015), where
2013). Kruppel like factor-8 (KLF-8) transcribes CXCR4 c-Myc regulates E-cadherin expression to promote an
to promote metastasis (Mukherjee et al., 2016) where stromal epithelial phenotype (Batsche et al., 1998). Transcription of
cell-derived factor-1 (SDF-1) can activate CXCR4 to MCC could hamper lymph node metastasis as silencing
promote EMT (Hu et al., 2014). The ETS transcription factor of this gene is associated with lymph node metastasis in
ETV-1 (ETS translocation variant-1) promotes stromal colorectal cancers (Benthani et al., 2018). Often epithelial
expansion and metastasis in PDACs (Heeg et al., 2016) versus mesenchymal states reflect the differentiation state
possibly through the SDF-1/CXCR4 axis. Likewise several of the cells. NK2 homeobox-1 (Nkx2-1) controls tumor
other EMT regulators were tightly linked to metastasis, differentiation and limits metastatic potential by repressing
including RUNX-2 (Runt-related transcription factor-2) the embryonically restricted chromatin regulator HMGA2 in
(Colden et al., 2017; Niu et al., 2012), TA-p63 (Su et al., a K-Ras background (Winslow et al., 2011). Likewise several
2010), Sp1 (Jiang et al., 2004; Jungert et al., 2007; Zhao et al., mesenchymal to epithelial transition (MET)-related factors
2016), Pea3 (polyomavirus enhancer activator-3 homolog) that contribute to an epithelial phenotype and negatively
(Zhang et al., 2013; Kwon et al., 2015), forkhead box Q1 regulate metastasis, including SPDEF (SAM pointed domain
(FOXQ1) (Qiao et al., 2011; Zhang et al., 2011) and pituitary containing ETS transcription factor) (Steffan et al., 2012),
transcript factor-1 (Pit-1) (Ben-Batalla et al., 2010). Often breast cancer metastasis-suppressor-1 (BRMS-1) (Liu et al.,
viruses like HPVs can deregulate ADP ribosylation factor 2012; Hsiao et al., 2017; Lei et al., 2017), YY-2 (Kakizaki
(Arf) expression to promote FOXM1 and execute EMT et al., 2016), TIEG (TGF-β-inducible early growth response
and metastasis (Raychaudhuri & Park, 2011; Jaiswal et al., protein-1) (Jin et al., 2012), p16 (Cui et al., 2015), TIP30 (HIV
2015). While most of these EMT events are directly linked to Tat-interacting protein 30 kDa) (Zhao et al., 2008), HMGB-1
TGF-ß, TGF-ß is also known to induce apoptosis. Notably, (high mobility group box-1) (Zuo et al., 2014) and XRP44X
phosphorylation-deficient STAT-3 blocks TGF-ß-induced (Semenchenko et al., 2016).
apoptosis as well as EMT (Yang et al., 2006), suggesting that Context-dependent function is very important in the
both apoptosis evasion and EMT are required for metastasis case of EMT/MET because while promoting an epithelial
once both these processes are commenced. phenotype in primary tumor cells may block invasion and
Apoptosis resistance also plays a major role in promoting metastasis, the same can promote metastatic colonization
metastasis (Fig. 3). A number of apoptosis-resistant in circulating tumor cells. For example, SIRT1 (Sirtuin-1)
genes/gene products regulating metastasis are presented blocks metastasis (Sun et al., 2013) but can also co-operate
in Table 1. K-Ras, VEGF-A, NRF2, c-IAP2, Sox-2, Sp1, YY1 with EMT to enhance metastasis (Byles et al., 2012).
and IGF1R are noteworthy as these genes promote survival Apoptotic cancer stem cells that undergo the blebbishield
during apoptosis or contribute to direct apoptosis resistance emergency program selectively suppress c-Myc during the
without committing to apoptosis (Jinesh et al., 2018b). Certain transformation phase (Jinesh et al., 2016c) but express c-Myc
transcription factors regulate both EMT and apoptosis and acquire epithelial morphology in blebbishield-derived
resistance to regulate metastasis. For example, Sp1 drives cells that exited the transformation phase (Jinesh et al.,
VEGF and vascular endothelial growth factor receptor-2 2013; Jinesh & Kamat, 2017b). Thus, context-dependent
(VEGFR2) transcription which is required for metastasis expression of c-Myc is tightly linked to the transformation
of pancreatic cancer cells (Wei et al., 2004) and to drive state of the cells (Fig. 2A). Furthermore, N-Myc expression
the blebbishield emergency program (Taoka et al., 2017) is crucial for blebbishield-mediated transformation (Jinesh
and EMT (Jungert et al., 2007). The Yin-Yang-1 (YY-1) et al., 2016c) and N-Myc downstream regulated gene-2
transcription factor can strategically regulate metastasis (Cho (NDRG2) loss inhibits metastasis (Li et al., 2018a). Induction

Table 2. Gene mutations as positive and negative regulators of metastasis
Metastasis
Mutant metastasis regulatory genes regulation Mechanism regulating metastasis
Combined APC, KRAS G12D , TGFBR2 Positive Combined effect on EMT and apoptosis resistance
a
TP53 Positive Amplification of c-Myc and Her2/ERBB2 activation
TP53-codon72 mutation Positive Promotes PGC-1α and mitochondrial function
TP53-R175H Positive Promotes TGF-β metastatic signaling by impeding anti-metastatic
transcription of p63, and by overcoming cell cycle arrest and
senescence
TP53-R273H Positive Promotes apoptosis resistance through NRP2
RASAL2 (K417E and K567X) Positive Mutants fail to suppress K-Ras/H-Ras-driven Ras/MAPK signaling
aCombined Rasal2−/− and Trp53+/− Positive Mutants fail to suppress K-Ras/H-Ras-driven Ras/MAPK signaling
TERT promoter Positive Enhanced transcription of TERT through ETS to prevent telomere
attrition
DR4 promoter Positive Alters Sp1 versus NF1 binding to promoter to regulate DR4 expression
and apoptosis
PIK3CA Positive Promotes apoptosis resistance by downregulating Bax
Combined BRAF V600E and PTEN loss Positive Co-operation to generate apoptosis resistance
Fas mutations Positive Promotes apoptosis resistance
Mitochondrial DNA mutations (MT-ND6) Positive Promotes ROS generation through defects in complex-I
FAK (Y925F) Negative Impairs FAK interaction with paxillin and impedes ERK/VEGF axis
L1 ectodomain mutations Negative Through CD10 signaling
MET (H1351N) Negative Mutation interferes with downstream signal transducer interactions
a
Cre/loxP recombinant technology-introduced defects in mice models; EMT, epithelial to mesenchymal transition; ROS, reactive oxygen
species.
of proper apoptosis inhibits cellular transformation and thus et al., 2018b) by mutations (Fig. 2C). The combination of p53
can inhibit metastasis. For example, nomilin treatment mutation and K-Ras activation can protect cells from mito-
can downregulate Bcl-2 (B-cell CLL/lymphoma-2), and chondrial apoptosis because p53 is needed to transcribe or
upregulates p53, Bax, caspase-9, caspase-3, p21, and p27 to stimulate mitochondrial-apoptosis mediators such as Bax
to suppress metastasis by inducing proper mitochondrial (Hacker et al., 2011), PUMA (Nakano & Vousden, 2001),
apoptosis (Pratheeshkumar, Raphael & Kuttan, 2012). and NOXA (Oda et al., 2000), whereas K-Ras redirects
Thus EMT and apoptosis are tightly linked to metastasis death receptor signaling into metastasis-promoting signal-
of cancer cells and can be positively or negatively regulated ing by blunting apoptosis (Hoogwater et al., 2010) through
by transcription in a context-dependent manner (Fig. 3). the blebbishield emergency program (Jinesh et al., 2016c).
TP53 mutations can also result in MYC amplification and
activation of epidermal growth factor receptor (EGFR) to
V. METASTASIS: THE GOOD, BAD AND UGLY promote metastasis (Lin et al., 2004). Alternatively, p53 codon
TRANSCRIPTS 72 mutation (P72R) can enable p53 to promote metas-
tasis through PGC-1α (peroxisome proliferator-activated
Apart from wild-type transcripts, a large body of evidence receptor γ coactivator-1-α) (Basu et al., 2018). In addition,
suggests that mutations drive metastasis predominantly TP53R175H mutation co-operates with TGF-ß/Smad signal-
through the regulation of EMT and apoptosis resistance ing and abrogates the anti-metastatic transcription of p63 to
by altered protein functions (Table 2). K-RasG12D muta- promote metastasis (Adorno et al., 2009; Melino, 2011) or by
tion drives liver metastasis of colorectal cancers, and overcoming cell cycle arrest and senescence (Morton et al.,
when associated with other mutant tumor suppressors 2010). Moreover, TP53R273H mutation promotes metastasis
(APC/adenomatosis polyposis coli, p53 and TGFBR2) by apoptosis resistance through VEGF-165 receptor NRP2
metastasis ability was greatly increased (Sakai et al., 2017). A (Neuropilin-2) (Lv et al., 2017a).
Ras-GTPase activating protein RASAL2 when mutated fails Next to TP53 and KRAS, TERT ranks as the third
to suppress Ras/MAPK signaling to promote metastasis. most mutated target among metastatic cancers according
Interestingly, RASAL2 co-operates with TP53 loss to promote to the MSK-IMPACT sequencing study (Zehir et al.,
metastasis (McLaughlin et al., 2013). In fact, p53 and K-Ras 2017). However, the mutations are within the promoter
were the most mutated genes among metastatic cancers region, introducing ETS (avian erythroblastosis virus
based on a huge Memorial Sloan-Kettering-integrated muta- oncogene homolog) transcription factor binding sites and
tion profiling of actionable cancer targets (MSK-IMPACT) resulting in enhanced TERT transcription and protection
sequencing study (Zehir et al., 2017) where p53 gets inacti- of chromosome telomeres (Zehir et al., 2017) (Fig. 2C).
vated (Zehir et al., 2017) and K-Ras gets activated (Jinesh Mutations in multiple other oncogenes and tumor suppressor

genes (PIK3CA, APC, ARID1A, PTEN , EGFR, KMT2D/C, (Lin-28 homolog B) and Zcchc11 (zinc finger CCHC
RB1, NF1, FAT1, BRAF , NOTCH1, KDM6A, KIT , CTNNB1, domain-containing protein-11) (Fu et al., 2014) to upregulate
BAP1, IDH1, GNAS and VHL) were also linked to metastasis Let-7 miRNAs that target K-Ras mRNA (Jinesh et al.,
by the MSK-IMPACT sequencing study (Zehir et al., 2017). 2018b; Zhou et al., 2017). This global miRNA regulation
Of these, PIK3CA, APC, PTEN , EGFR, KMT2D/C, RB1, overcomes apoptosis resistance, illustrating the dominant
NF1, FAT1, BRAF , NOTCH1, KDM6A, KIT , CTNNB1 and role of apoptosis resistance in metastasis in the context
VHL) are directly or indirectly (through K-Ras) related to of miRNAs because LIN28B inhibits apoptosis (Lin et al.,
Wnt-signaling-linked EMT and apoptosis resistance where 2018). Apoptosis resistance is also thwarted by miR-770 by
the regulation of ß-catenin-dependent transcription is altered targeting STMN1 (stathmin-1) to suppress metastasis (Li
(Cizkova et al., 2011; Morris et al., 2013; Zhan, Rindtorff et al., 2018b). In addition to metastasis suppression, miRNAs
& Boutros, 2016). For example, BRAF V600E mutation can also promote metastasis by promoting apoptosis
co-operates with PTEN loss, and overcomes apoptosis resistance. For example, miR-886 inhibits apoptosis and
to promote metastasis of melanoma cells (Dankort et al., activates the JAK2/STAT-3 axis to promote metastasis (Lei
2009). Similarly activating mutations in PIK3CA overcome et al., 2017). In response to genotoxic treatments, miR-181a
apoptosis by downregulating BAX expression to promote is upregulated through STAT-3-mediated transcription,
metastasis (Guo et al., 2007). Death-promoting receptors and the miRNA in turn targets Bax to combat apoptosis and
(death receptor-4/DR4 promoter and Fas) can mutate generate therapy resistance and metastasis (Niu et al., 2016).
to promote metastasis by conferring apoptosis resistance Metastasis-suppressive functions of death activated protein
(Shin et al., 2002; Wu et al., 2018). Apoptosis resistance is kinase (DAPK) and KLF-4 are targeted by miR-103/107
mainly conferred by protecting mitochondria from intrinsic to promote metastasis by preventing anoikis-mediated cell
apoptosis through the blebbishield emergency program death (Chen et al., 2012). Thus miRNAs both positively
(Jinesh et al., 2016a,c): an innovative study identified that and negatively regulate apoptosis to inhibit or promote
transferring mitochondria with mutations in MT-ND6 from metastasis (Table 3).
highly metastatic cells to benign cells promoted metastasis Similarly, in the context of EMT, a number of miRNAs
of benign cells through regulation of reactive oxygen that suppress EMT also inhibit metastasis. For example,
species (ROS) generation due to defective complex-I of the miR-466 targets the EMT-related transcription factor
respiratory chain (Ishikawa et al., 2008). Fusion transcripts RUNX-2 to suppress prostate cancer metastasis (Colden
such as RRM2-c2orf48 also can promote lung and lymph et al., 2017) (Table 3). Expression of miR-543 targets K-Ras
node metastasis in a mouse model (Matei, Kim & Lyden, and HMGA2 to block metastasis (Fan et al., 2016). ZEB1 (zinc
2017). A-to-I RNA editing impedes the expression of finger E-box binding homeobox-1), an EMT inducer, blocks
SLC22A3 (solute carrier family-22A3) to promote metastasis E-cadherin to promote metastasis (Wu et al., 2012; Yang et al.,
of oesophageal squamous cell carcinoma (Fu et al., 2017). 2014) which in turn is targeted by miR-200 family miRNAs
Truncation mutation also can promote metastasis, as in the (Park et al., 2008). Alternatively, miR-200b can also suppress
case of APC (Schell et al., 2016). metastasis through targeting the ERM (ezrin, radixin,
On the other hand, mutations can also impede metastasis. moesin family) protein moesin (Li et al., 2013). SNAI2, an
For example, point mutation (H1351N) in MET can EMT transcription factor, is targeted by miR-203 to block
abrogate metastasis (Giordano et al., 1997), FAK Y925F lung metastasis (Ding et al., 2013). VEGF-induced Sox-2
mutation impedes the extracellular signal-regulated kinase impedes the metastasis negative-regulatory miRNA-452 to
(ERK)/VEGF axis to block metastasis (Kaneda et al., 2008), promote lung metastasis (Kim et al., 2017). The metastasis
and L1 ectodomain mutations also impede metastasis negative-regulatory miRNA pair miR-144/451 act by
through CD10 signaling (Haase et al., 2016). Thus alterations targeting mRNAs of extracellular matrix proteases ADAM10
in genes and RNAs can positively or negatively regulate (a disintegrin and metalloproteinase domain-10) and
metastasis depending upon the nature of the mutation and ADAMTS5 (ADAM metallopeptidase with thrombospondin
the target gene/RNA involved. type-1 motif-5) which mediate migration and metastasis
(Zhang et al., 2015c). Metastatic cancers suppress miR-148a
and miR-34b/c by hypermethylation to enable metastasis
VI. NON-CODING RNAs AND through changes in the methylation signature (Lujambio
SUPER-REGULATION OF METASTASIS et al., 2008). DeltaNp63alpha transcription factor lacking a
transactivation domain represses miR-527 and miR-665 to
Non-coding RNAs have emerged as critical regulators of promote TGF-ß signaling-mediated EMT and metastasis
protein-level gene expression, including miRNAs, lncRNAs, (Rodriguez et al., 2016). By contrast, EMT-driven metastasis
large intervening non-coding RNA (lincRNAs), small can also be promoted by miRNAs: for example, elevated
nucleolar RNAs (snoRNAs), ceRNAs, and circular RNAs miR-199a downregulates FOXP2 expression levels to
(circRNAs). Non-coding RNAs either target apoptosis or promote EMT and metastasis (Cuiffo et al., 2014). FOXO3
EMT/MET, or both, to regulate metastasis (Table 3). is downregulated by miR-182 to result in the promotion of
Global miRNA upregulation associated with miR-26a EMT and metastasis (Segura et al., 2009; Ni et al., 2014). In
suppresses metastasis through targeting LIN28B addition, miR-373 was identified as a metastasis-promoting

Table 3. Non-coding RNAs that positively and negatively regulate metastasis through epithelial to mesenchymal transition (EMT)
and apoptosis resistance

non-coding RNAs regulation Mechanism of metastasis regulation
miR-886 Positive Inhibits apoptosis and activates JAK2/STAT-3 pathway
miR-199a Positive Targets FOXP2 to promote EMT and metastasis
miR-373 Positive CD44 expression a possible target to promote metastasis
miR-520c Positive Target(s): NDa
miR-224 Positive Target: USP3, promotes metastasis through Smad4 signaling
miR-181a Positive Target: BAX to suppress apoptosis
miR-103/107 Positive Targets: DAPK and KLF4 to blunt anoikis-mediated apoptosis
miR-499 Positive Targets: FOXO4 and PDCD4
lncRNA-HOTTIP Positive Target: HOXA13, an EMT regulator
lncRNA-HOTAIR Positive Targets CDK5 by H3K27me3 to promote EMT
lncRNA-ATB Positive Target: ZEB1/2, an EMT inducer
lncRNA-treRNA Positive Target: CDH1/E-cadherin; through induction of EMT
lncRNA-AB073614 Positive Target: BAX; through induction of apoptosis resistance
lncRNA-MALAT1 Positive Target: Nrf-2; through induction of apoptosis resistance
lncRNA-H19 Positive Target: miR-106a-5p; through induction of glycolytic phenotype; also acts as ceRNA to
miR-29b-3p
lncRNA-CCAT2 Positive Target: TCF7L2; through apoptosis resistance and chromosomal instability
lncRNA-TRINGS Positive Target: STRAP–GSK3β –NF-κB; through protection from necrosis
lncRNA-ZFAS1 Positive Target: miR-486; pro-apoptotic miR-486 is sponged to induce apoptosis resistance
lncRNA-ANRIL Positive Target(s) NDa; through induction of apoptosis resistance
lncRNA-BCYRN1 Positive Target: MMP9 and MMP13; promotes invasion and migration
lncRNA-MALAT1 Positive Target: multiple prometastatic factors
lncRNA-EWSAT1 Positive Target: lncRNA-MEG3
lncRNA-HULC Positive Target: miR-200a/ZEB1 to promote EMT
lncRNA-ATB Positive Target: miR-494 and miR-126 to promote EMT and apoptosis resistance
lncRNA-MIAT Positive Target: miR-141, miR-132 and miR-133 to promote apoptosis resistance
lncRNA-BORG Positive Target: TRIM28 to promote repression of target genes
lncRNA- ZEB2-AS Positive Target: ZEB2 mRNA to promote translation and EMT
lncRNA- BCAR4 Positive Target: Vimentin, and E-cadherin to promote EMT
linc-ZNF469-3 Positive Target: ZEB1 through miR-574-5p to regulate EMT
linc-ROR Positive Target: acts as ceRNA to miR-205 to induce ZEB2, an EMT inducer
lincRNA-00273 Positive Target: TGF-β signaling; thus works through EMT
snoRNA-SNORA23 Positive Target: SYNE2; promotes spheroid formation and thus induces apoptosis resistance
circRNA-CCDC66 Positive Target(s) NDa; through regulation of oncogenes and tumor suppressor genes
circRNA-0016347 Positive Target: miR-214; upregulates caspase-1
miR-466 Negative Targets RUNX2 mRNA to suppress metastasis
miR-543 Negative Targets KRAS and HMGA2 mRNAs to suppress metastasis
miR-200 family Negative Targets ZEB1 mRNA to suppress metastasis
miR-200b Negative Targets Moesin mRNA to suppress metastasis
miR-182 Negative Targets FOXO3 mRNA to suppress metastasis
C14MC clusterb Negative Target(s): NDa
miR-203 Negative Targets SNAI2 mRNA to suppress EMT and metastasis
miR-452 Negative Sox-2 suppresses miR-452 to promote metastasis
miR-144/451 Negative Targets ADAM10 and ADAMTS5 mRNA to suppress migration and metastasis
miR-148a and miR-34b/c Negative Targets c-MYC, E2F3, CDK6, and TGIF2; methylation of miR-148a and miR-34b/c promotes
metastasis
miR-527 Negative Targets Smad4 and TGF-βRII to block EMT
miR-665 Negative Targets Smad4 and TGF-βRII to block EMT
miR-26a Negative Targets LIN28B and Zcchc11 to allow Let-7 maturation
miR-Let-7 Negative Targets KRAS to overcome apoptosis resistance
miR-12528 Negative Target: IGF1R to target migration and apoptosis
miR-770 Negative Target: STMN1 to overcome apoptosis resistance
miR-30a Negative Target: Beclin1 and ATG5 to suppress autophagy
miR-10a Negative Targets: MMP14 and ACTG1
lncRNA-LET Negative Targets hypoxia signaling; promotes apoptosis
lncRNA-MEG3 Negative Target: miR-21
lncRNA-GAS5 Negative Target: miR-221 to suppress EMT
lncRNA-SPRY4-IT1 Negative Target: E-cadherin and vimentin to suppress EMT
lncRNA-MALAT1 Negative Targets prometastatic transcription factor TEAD
linc-00974 Positive Target: KRT19 to promote apoptosis resistance and TGF-β signaling (EMT)
ceRNA-from CCR2 Negative Targets Rho/ROCK signaling to inhibit EMT
USP3-3’-UTR Negative Targets miR-224 by sponging and block Smad4 signaling by acting as ceRNA
C14MC, chromosome 14 miRNA cluster;

a
ND, not determined.
b
The individual miRNAs from this cluster may have metastasis promoting or suppressive functions, as it is a large miRNA cluster.

miRNA possibly by targeting CD44 expression (Huang et al., can act on sense transcripts to regulate gene function.
2008). For example, the anti-sense lncRNA-ZEB2-AS restores
Many other miRNAs such as miR-12528 (Jeon et al., ZEB2 translation to promote EMT and metastasis (Wei-
2018), and miR-499 (Liu et al., 2011) also target metastasis dle et al., 2017). Conversely, treRNA (translation regulatory
by directly or indirectly targeting EMT and or apoptosis lncRNA) promotes metastasis by suppressing the translation
(Table 3). Autophagy regulates both apoptosis and EMT, of E-cadherin mRNA (Gumireddy et al., 2013) and thereby
and miR-30a targets autophagy by suppressing Beclin1 influences EMT.
and ATG5 (autophagy related-5) to abrogate metastasis Similarly, lncRNAs can negatively regulate EMT and
(Fu et al., 2018). Similarly miR-10a targets both EMT and metastasis. For example, lncRNA-DREH acts as a metas-
anoikis resistance to suppress metastasis (Liu et al., 2017). tasis negative-regulatory RNA by interfering with vimentin
In addition, large clusters of miRNAs which are highly expression (Huang et al., 2013), and lncRNA-GAS5 sup-
co-regulated in expression may harbor individual miRNAs presses metastasis by reversing EMT through miR-221
with contradictory functions over metastasis. For example, (Liu et al., 2018b). lncRNA-SPRY4-IT1 from the intron
the largest miRNA cluster found in the human genome of SPRY4 suppresses metastasis by interfering with EMT,
on chromosome 19q13.42 (C19MC: which harbors 46 whereas EZH2 represses SPRY4-IT1 expression through
miRNAs) is blocked from expression by imprinting by H3K27me3 modification to promote metastasis (Sun et al.,
CpG island methylation in normal tissues (Noguer-Dance 2014). MALAT1 (metastasis-associated lung adenocarci-
et al., 2010) but is expressed in metastasis (Vaira et al., 2012) noma transcript-1) suppress E-cadherin to promote EMT
and therapy-resistant triple negative breast cancers (TNBCs) (Ji et al., 2003) and regulate metastasis-associated genes to
(Jinesh et al., 2018a). While most miRNAs from C19MC promote metastasis in lung cancer (Gutschner et al., 2013).
are not yet characterized in the context of metastasis, However in breast cancer MALAT1 suppresses metasta-
miR-520c was found to promote breast cancer metastasis sis (Kim et al., 2018), indicating a tumor-type-dependent
(Huang et al., 2008) and miR-520G was found to lead function. There are examples where one lncRNA antago-
to therapy resistance in colon cancer cells (Zhang et al., nizes another lncRNA to regulate metastasis. For example,
2015b). Paradoxically another C19MC miRNA, miR-526B, lncRNA-MEG3 inhibits metastasis (Dan et al., 2018) but
is known to promote p53 to suppress lung cancers (Zhang lncRNA-EWSAT1 suppresses lncRNA-MEG3 to promote
et al., 2015a). Thus individual miRNAs from this cluster might metastasis (Sun et al., 2016b). Similarly many lncRNAs,
act independently in the context of metastasis. However, such as lncRNA-BCAR4 (N. Li, Gao & Liu, 2017a) and
another miRNA cluster on chromosome-14 (C14MC) is linc-ZNF469-3 (Wang et al., 2018), promote or suppress
expressed following epigenetic changes and can suppress the EMT and metastasis illustrating the prominent genetic con-
metastatic properties of cancers (Oshima et al., 2018). Thus, trol of metastasis via EMT (Table 3).
in the context of metastasis, the overall effect of miRNA Apoptosis is also a target for lncRNAs to regulate
clusters may differ depending on cellular context and cancer metastasis. For example, lncRNA AB073614 downregulates
type. To summarize, the predominant mode of action in the Bax expression and is associated with distant metastasis
regulation of metastasis by miRNAs is by regulation of EMT rather than with lymph node metastasis (Wang et al., 2017).
and apoptosis (Table 3). The malignancy-associated lncRNA MALAT1 activates
Similarly, transcriptional and post-transcriptional regula- the Nrf-2 antioxidant pathway (Zeng et al., 2018) to
tion of lncRNAs can positively or negatively regulate metas- prevent ROS-provoked apoptosis (Jinesh et al., 2018b).
tasis through regulation of EMT and apoptosis (Table 3). In In malignant melanoma, lncRNA H19 directs glucose
the context of positive regulation of EMT and metastasis, the metabolism through miR-106a-5p (Luan et al., 2018), a
EMT regulator HOXA13 (homeobox-A13) facilitates metas- process characteristic of metastatic cancer cells (Pavlides
tasis via the lncRNA HOTTIP (Lin et al., 2017). TGF-ß an et al., 2012) to evade secondary necrosis during the
EMT-inducing cytokine, activated lncRNA-ATB to enable blebbishield emergency program (Jinesh et al., 2016c).
prometastatic action by ZEB1/2 in hepatocellular carcinoma Colon cancer cells overexpressing lncRNA-CCAT2 (colon
cells (Yuan et al., 2014). Furthermore, lncRNA-HULC pos- cancer associated transcript-2) undergo liver metastasis
itively regulated metatsasis by promoting EMT through and chromosomal instability (Ling et al., 2013) where
miR-200a and ZEB1 in hepatocellular carcinoma (Li et al., CCAT2 is an anti-apoptotic factor (Lang et al., 2017). In
2016; Parsons et al., 2018). Similarly, lncRNA-BORG pro- contrast to the tumor-suppressive role of p53, p53-inducible
motes metastasis by repressing a set of target genes through lncRNA-TRINGS (TP53-regulated inhibitor of necrosis
TRIM28 (tripartite motif containing-28) (Gooding et al., under glucose starvation) protects cells from necrosis during
2017). Often lncRNAs target more than one metastasis glucose starvation (Khan et al., 2017) raising the possibility
regulatory miRNA to promote or prevent metastasis; for that TRINGS could play a role in the blebbishield emergency
example, lncRNA-ATB impedes miR-494 (Cao et al., 2018) program or hypoxia pathway and metastasis. In addition,
and miR-126 to promote metastasis (Zheng et al., 2019). the lncRNA ZFAS1 (ZNFX1 antisense RNA-1) promotes
Furthermore, lncRNA-MIAT targets miR-132, miR-133 metastasis in hepatocellular carcinoma (Li et al., 2015) and is a
and miR-141 to promote metastasis (Sha et al., 2018; Liu sponge for miR-486 which induces apoptosis (Sun et al., 2017;
et al., 2018a; Li, Liu & Fu, 2018c). Anti-sense lncRNAs Li et al., 2017b). The lncRNA-ANRIL, an anti-apoptotic

factor, was found enriched in non-small cell lung cancer mesenchymal-to-epithelial transition (MET) (Gao et al.,
metastases (Nie et al., 2015). lncRNA-LET, an apoptosis 2016).
regulator, also interferes with hypoxia signaling to block Enhancers and super-enhancers also can contribute to
metastasis and this lncRNA is downregulated in HCC, CRC metastasis and there appears to be a required change in
and lung cancers (Yang et al., 2013). enhancer activity for metastasis (Kovar, 2018; Morrow et al.,
Other non-coding RNAs also regulate metastasis 2018). Histone acetylation is a marker of enhancers and
(Table 3). For example, silencing of lincRNA-ROR ham- euchromatin regions of local and distant metastatic cells
pered lung metastasis to demonstrate the pro-metastatic show marked differences in H3K27ac pattern in PDAC
role by regulating EMT (Hou et al., 2014). The (Alderton, 2017).
snoRNA SNORA23 promotes the expression of spectrin Copy number variation is one major cause that can
repeat-containing nuclear envelope 2 (SYNE2) to aug- promote oncogene function to favor metastasis. Copy
ment liver metastasis of pancreatic ductal adenocarcinoma number variation can occur through structural alteration
(Cui et al., 2017). linc-RNA-00974 affects apoptosis resis- in chromosomes by rearrangements that result in tandem or
tance and EMT to promote metastasis (Tang et al., 2014). interspersed repeats generated through extra-chromosomal
linc-RNA-00273 promotes metastasis through TGF-ß sig- propagation and reintegration of oncogenes (e.g. EGFRvIII)
naling and can be inhibited by G-quadruplex formation (Turner et al., 2017) and contribute to metastasis (Liu
(Jana et al., 2017). ceRNAs generated from CCR2 (receptor et al., 2016). Apart from structural changes resulting in
of C-C motif chemokine ligand-2) blocks the RhoGT- chromosomal instability, numerical changes also contribute
Pase activating proteinP/Rho/Rho-associated coiled-coil to metastasis. Complex ploidy-level chromosomal instability
domain containing protein kinase-1 (ROCK) /STARD13 can contribute to metastasis (Bakhoum et al., 2018) through
(StAR-related lipid transfer domain containing-13)/F-actin the blebbishield emergency program (Jinesh & Kamat,
axis to inhibit EMT and metastasis of breast cancer cells (Hu 2017b), or through a cytosolic DNA response, independent
et al., 2017). Ubiquitin specific peptidase-3 (USP3) loss due to of aneuploidy (Bakhoum et al., 2018). Multiple cancer types
miR-224 action leads to metastasis, and the expression of the are known to accumulate additional copies of chromosome-8
3 -untranslated region (UTR) of USP3 blocks metastasis by that harbors the Myc oncogene (Jinesh et al., 2018b) which
acting as ceRNA for Smad-4 (Z. Wang et al., 2017b) (Fig. 2B). regulates metastasis through the lncRNA BCYRN1 (brain
The lncRNA-H19 acts as ceRNA to miR-29b-3p to promote cytoplasmic RNA-1) (Hu & Lu, 2015). Thus individual
metastasis (Lv et al., 2017b). Circular RNAs (circRNAs) such copy-number variation should be interpreted with caution
as CCDC66 (coiled-coil domain containing-66) (Hsiao et al., in the context of structural and numeric chromosomal
2017; Kristensen et al., 2018), FECR1 (FLI1 exonic circular instability.
RNA) (Chen et al., 2018) and hsa-circ-0016347 (Jin et al., Loss of imprinting control can promote the expression
2017) promote metastasis in colon cancer, breast cancer and of hidden genes that can unleash critical regulators of
osteosarcoma, respectively. tumorigenesis and metastasis. IGF-2 mRNA and H19
Thus non-coding RNAs predominantly regulate metas- lncRNA arise from imprinted genes (Wianny et al., 2016)
tasis through super-regulation of EMT and apoptosis- and their expressions are tightly linked to cancer progression
regulatory RNAs. and metastasis (Matouk et al., 2014; Li et al., 2017). H19
expression is associated with enhancer activation which
marks the loss of imprinting control and CpG methylation
VII. METASTASIS: THE MISSING, (Engel et al., 2004). Loss of imprinting control unmasks the
SUPER-EXPRESSED AND IMPRINTED expression of carcinoembryonic antigens (e.g. cell adhesion
TRANSCRIPTS molecules such as CEACAM), which in-turn promote
metastasis by promoting oncogene function (Arabzadeh
et al., 2013; Beauchemin & Arabzadeh, 2013; Chiang et al.,
Chromosomal deletions can disable crucial tumor 2018). H19 expression controls EMT and MET phenotype
suppressors resulting in missing transcripts that can conversions (Matouk et al., 2016) by behaving as ceRNA to
suppress metastasis if expressed. Chromosome-5q deletion miR-29b-3p (Lv et al., 2017b) and IGF-2 controls stem cell
results in the loss of miRNA-3607 which controls the expansion aspects (Murayama et al., 2016) and metastasis (X.
prometastatic Src kinase (Saini et al., 2014; Zhang et al., Li et al., 2017). However, the role of these imprinted genes
2017a). Another prominent example is Chr.17p loss needs additional studies to track their exact function in the
(harbors TP53) which is preceded by mutations in context of cancer.
APC and ß-catenin accumulation (Rivlin et al., 2011).
Defective or missing p53 and APC transcripts are leading
contributors to pan-cancer metastasis (Schell et al., 2016;
Zehir et al., 2017). Even more interestingly, reversible VIII. HARNESSING GENETIC CONTROL OVER
epithelial and mesenchymal phenotypes (required for METASTASIS FOR THERAPY
distant metastasis) were demonstrated to be associated with
chromosomal instability, where deletion of chromosome-10p Metastasis involves the relocation of cancer (stem) cells
results in the loss of the ZEB1 gene that promotes from primary tumors to distant or local lymphoid or

Table 4. Anti-metastatic agents targeting cancer metastasis through genetic mechanisms
Anti-metastastic agent Cancer type/model system Mechanism to inhibit metastasis

Metarrestin Pancreatic cancer in mouse model Destructs perinucleolar compartment of nucleoli (sites of active
transcription) and inhibits RNA-Pol-I-dependent
transcription
Intra-venous NET-digesting, Breast cancer in mouse model Destructs NET DNA to inhibit NET DNA-mediated
DNase I-coated promotion of metastasis
nanoparticles
Mithramycin-A Lung cancer cells Destructs DNMT-1 expression to protect tumor-suppressor
genes from CpG-island hypermethylation
Intranasal or peritumoral Melanoma in mouse model Inhibits metastatic cells through CD4+ and CD8+ T cells by
CpG oligonucleotides inducing T-cell activating cytokine IFN-γ
shRNA against S100P Non-small cell lung cancer in mouse Inhibits S100P and hence likely impedes calcium signaling
model
Intratumoral siRNA plasmid Murine mammary cancer Inhibits microvessel density by targeting VEGF-C mRNA, and
against VEGF-C hence targets angiogenesis
Calcium phosphate hybrid Breast cancer mouse model By regulating the expression of metastasis-related genes and
micelle-PRDM14 RNAi reducing methylation of tumor-suppressor genes.
miR-10b antagomirs Breast cancer mouse model By relieving the suppressive effect of miR-10b on Hoxd10
M2 (bis Schiff base) Melanoma in mouse model LINC00273 promoter G-quadruplex stabilization by M2
Decitabine (DNMT inhibitor) Osteosarcoma in mouse model Relieves epigenetic silencing of ER-α and suppresses metastasis
in an ER-α-dependent manner
5-Aza-2 -deoxycytidine Lung and liver metastasis of Unmasks epigenetic silencing of C14MC to suppress metastatic
(5-Aza-dC, Decitabine) colorectal cancer cells properties
Nomilin Melanoma metastasis to lungs in Promotes p53-dependent transcription to induce proper
mouse model apoptosis
MALAT1 antisense Lung cancer metastasis in mouse Targets MALAT1-regulated metastasis-associated gene set
oligonucleotides model
C14MC, chromosome 14 miRNA cluster; DNMT, DNA methyltransferase; NET, neutrophil extracellular trap.
other sites. Cancer cells learn to migrate, colonize target EMT and resistance to cell death could be targeted
sites, survive, evade genomic instability checkpoints, evade by G-quadruplex stabilization or relaxation by helicases
immunity and achieve/maintain an immortal phenotype. (at the RNA level and/or DNA level). For example,
Among these hallmark properties of metastasis, migration the G-quadruplex in hnRNPF (heterogeneous nuclear
and colonization at target sites are regulated by EMT ribonucleoprotein-F) inhibits EMT (Huang et al., 2017),
and MET. Survival, genomic-instability-checkpoint evasion, and the G-quadruplex in TERT inhibits telomerase
immune evasion and high glycolytic phenotype are regulated transcription (Marcel et al., 2011; Saha et al., 2017). In
by the blebbishield emergency program. An immortal this context, targeting G-quadruplex stabilization is an
phenotype is regulated by TERT transcription. These emerging and attractive area of cancer therapeutic research
events are often triggered by epigenetic changes, and some where G-quadruplex stabilization by M2 (bis Schiff base)
epigenetic drugs/RNA interference (RNAi) agents are able can inhibit metastasis by targeting LINCRNA00273
to inhibit metastasis in multiple cancer types. Mithramycin-A expression (Jana et al., 2017). However, G-quadruplex
(Lin, Hsu & Wang, 2007), PRDM14 (PR/SET domain-14) stablilization is unlikely to involve a single target. Inhibiting
RNAi (Taniguchi et al., 2017) and 5-Aza-2 -deoxycytidine the telomerase transcription that gives an immortal
(Lillo et al., 2018; Oshima et al., 2018) are able to inhibit phenotype to cancer/metastatic cancer cells is also an
metastasis by overcoming epigenetic silencing of key attractive option. For example, TMPyP4 [tetratosylate,
tumor suppressors/miRNA clusters (Table 4). To add meso-5,10,15,20-tetrakis-(N-methyl-4-pyridyl)porphine]
more support to the epigenetic control of metastasis, porphyrin targets the TERT G-quadruplex for stabilization
CpG oligonucleotides were shown to promote T-cell (Mikami-Terao et al., 2008). The G-quadruplex in RNAs
activation via interferon-γ (IFN-γ ) to suppress metastasis can act in different ways depending on the function of the
(Kunikata et al., 2004; Zhou et al., 2010) (Table 4). Targeting gene product. For example, the TP53 intron-3 prevents
neutrophils and possibly other NET-forming cells by the generation of alternative splicing-induced delta isoforms
DNAse-I coated nanoparticles is also a useful strategy to of p53 that can act as dominant negative mutants in
curb metastasis (Park et al., 2016). Interestingly Metarrestin which the TA isoform cannot induce proper apoptosis
targets general transcription by targeting the perinucleolar (Marcel et al., 2011). In the case of VEGF mRNA, the
transcription compartment (Huang et al., 1998; Frankowski G-quadruplexes can promote IRES-dependent translation
et al., 2018), illustrating the powerful role of transcription in of VEGF, which can in turn promote apoptosis resistance
metastasis. and metastasis. Thus a G-quadruplex-targeting approach

must be fine-tuned toward target mRNAs, using guides as in (2) Metastasis is powerfully regulated at the RNA and
CRISPR (clustered regularly interspaced short palindromic transcription levels.
repeats) technology. Tian et al. (2018) discuss more chemical (3) Emergency transcription and associated IRES
targeting options for G-quadruplex structures. Targeting translation promote survival during apoptosis and regulate
Bloom syndrome–associated helicase (BLM), Werner malignant transformation of metastatic cells.
syndrome-associated helicase (WRN) and regulator of (4) Metastasis is tightly regulated at RNA levels depending
telomere length 1 (RTEL1) are alternative options as these on whether the target mRNAs are oncogenic or tumor
helicases relax G-quadruplex structures of the TERT gene suppressor in nature.
(Vannier et al., 2012; Drosopoulos et al., 2015; Wu et al., (5) Non-coding RNAs exhibit a super-regulatory role
2015). Cancer-specific delivery of RNAi to these helicases is over metastasis-regulatory RNAs to control or promote
a safer option than systemic delivery because much remains metastasis.
to be understood about the functions of these helicases in (6) Chromosomal aberrations, mutations and chromoso-
normal physiology. mal imprinting can modulate metastasis by altering the copy
RNAi therapeutics is an emerging area of research in number and functionality of critical RNA transcripts.
which non-coding RNAs can be effectively used against (7) The functions of non-coding RNAs, transcription
pivotal RNA molecules that drive tumorigenesis and or inhibitors and epigenetic modulators can be utilized as
metastasis. For example, preclinical short hairpin RNA efficient and sustainable therapeutic options.
(shRNA)-adjuvant therapy prevents NSCLC metastasis
(Bulk et al., 2008). More target-directed approaches can be
achieved using shRNAs (Bulk et al., 2008), miRNAs (Ma et al., X. CONFLICT OF INTEREST
2010), siRNAs (Shibata et al., 2013), and oligonucleotides
(Gutschner et al., 2013) against metastasis regulatory mRNAs The authors declare no conflicts of interest.
(Table 4). However, some RNAi agents might act on other
targets and hence a thorough pre-clinical study is essential
to implement this approach. Alternatively miRNA zippers XI. AUTHOR CONTRIBUTIONS
that can sponge more than one miRNA or non-coding
RNA or mRNA can be designed to target crucial drivers All authors contributed equally.
of tumorigenesis and metastasis (Meng et al., 2017). While
designing miRNA zippers, the seed sequences should be
kept in mind rather than using a pre- or mature miRNA.
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(Received 1 October 2018; revised 24 September 2019; accepted 26 September 2019; published online 30 October 2019)

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1469185x, 2020, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/brv.12562 by CAPES, Wiley Online Library on [20/12/2022].

The genetic script of metastasis

I. INTRODUCTION tumorigenesis and metastasis share many properties in

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Metastasis regulatory Type of metastasis

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Metastasis regulatory Type of metastasis

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Table 2. Gene mutations as positive and negative regulators of metastasis

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Metastasis regulatory Type of metastasis

C14MC, chromosome 14 miRNA cluster;

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Table 4. Anti-metastatic agents targeting cancer metastasis through genetic mechanisms

Anti-metastastic agent Cancer type/model system Mechanism to inhibit metastasis

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

Biological Reviews 95 (2020) 244–266 © 2019 Cambridge Philosophical Society

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