Cancer Cell

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Dynamic ROS Regulation by TIGAR:

Balancing Anti-cancer and Pro-metastasis Effects
Sarah-Maria Fendt1,2 and Sophia Y. Lunt3,4,*
1Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven,

Belgium
2Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI),

Herestraat 49, 3000 Leuven, Belgium

3Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
4Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA

*Correspondence: sophia@msu.edu
https://doi.org/10.1016/j.ccell.2020.01.009

The role of ROS in cancer is complex, with studies demonstrating both pro- and anti-tumor effects. In a
pancreatic ductal adenocarcinoma model, ROS limitation through TIGAR has been shown to initially support
cancer development but to later become a metabolic liability in metastasizing cells that is counteracted by
decreased TIGAR expression.

Reactive oxygen species (ROS) have
been present since aerobic organisms
began generating energy by passing elec-
trons from metabolic fuel sources to oxy-
gen. While transferring electrons from
various metabolites to O2 releases much
greater levels of energy than anaerobic
catabolism, the process of transferring
electrons through the electron transport
chain is not 100% efficient and generates
ROS. ROS can cause oxidative damage
and lead to cell death; thus, cells have
anti-oxidant mechanisms in place to pre-
vent oxidative damage. On the other
hand, ROS can also promote proliferation
and survival. An imbalance in ROS levels
can lead to premature aging and
numerous diseases, including cancer
and its progression toward metastasis
formation (Elia et al., 2018; Teoh and
Lunt, 2018).
While ROS can impact cancer cell sur-
vival, migration, and proliferation, whether
they promote or impede tumors is com-
plex. ROS can contribute to cancer initia-
tion by causing DNA damage, and further
promote cancer growth by activating
signaling pathways for proliferation. On
the other hand, studies have also demon-
strated high levels of oxidative stress in
cancer development and the need for up-
regulated antioxidant defense pathways
in tumors. Accordingly, some chemother-
apeutic agents rely on ROS generation to
target cancer cells. Adding to the
complexity, some studies have shown
that increased ROS promotes metastasis,
while others show that ROS limitation is
the key to metastasis. Specifically, mito-
chondrial DNA mutations that cause over-
production of ROS resulted in enhanced
metastatic potential in mice (Ishikawa
et al., 2008), and oxidative stress medi-
ates secretion of factors that promote in-
vasion in mammary organoids and zebra-
fish models (Arnandis et al., 2018).
Conversely, oxidative stress was shown
to limit distant metastasis of human mela-
noma cells in immunodeficient mice (Pis-
kounova et al., 2015), and administering
antioxidant N-acetylcysteine in a mouse
model of melanoma increased metastasis
(Le Gal et al., 2015). Moreover, activation
of NRF2, a transcription factor that acti-
vates antioxidant defense, stimulated
lung cancer metastasis by inhibiting the
degradation of BACH1, a pro-metastatic
transcription factor (Lignitto et al., 2019),
and stabilizing BACH1 using antioxidants
promoted lung cancer metastasis (Wiel
et al., 2019). The conflicting findings of
various studies points to the complexity
in understanding the effects of ROS in
cancer, which likely depend on many fac-
tors such as tumor type, genetics, epige-
netics, microenvironment, stage, vascu-
larization, and immune modulation.
In this issue of Cancer Cell, Cheung and
colleagues clarify the role of an antioxi-
dant defense pathway in pancreatic can-
cer development and metastasis (Cheung
et al., 2020). They focus on TIGAR, a bi-
sphosphatase that activates the oxidative
pentose phosphate pathway to generate
antioxidant NADPH, which has been
found at high levels in several cancer
types. Cheung and colleagues find that
high levels of TIGAR first promote pancre-
atic cancer initiation by limiting ROS and
that low levels of TIGAR later promote
the metastatic capacity of pancreatic
cancer cells by enhancing ROS (Figure 1).
In a pancreatic cancer model, deletion of
Tigar increased ROS and decreased pre-
malignant PanIN lesions but enhanced
metastatic ability. This builds on their pre-
vious finding that enhancing ROS through
loss of NRF2 suppressed PanIN develop-
ment (DeNicola et al., 2011). Consistent
with enhanced metastatic ability, Tigar
null pancreatic cancer cells acquired a
mesenchymal phenotype and activated
Erk signaling through the reduction of
the phosphatase Dusp6/MKP-3. More-
over, Tigar null, but not wild-type, pancre-
atic cancer cells showed reduced lung
metastasis formation upon antioxidant
treatment. It is possible that TIGAR re-
expression may further support prolifera-
tion of metastasized cells at the second-
ary site.
Cheung and colleagues demonstrate
the new concept that dynamic ROS regu-
lation through antioxidant defense mech-
anisms is required for pancreatic cancer
development and spread to distant or-
gans. Their findings imply that, contrary
to previous findings in melanoma and
lung cancer, antioxidant administration
may be beneficial for reducing lung
metastasis formation in pancreatic tu-
mors with low TIGAR expression. More-
over, specific types of ROS will likely
have diverse effects on different cancer
types throughout development and meta-
static spread. Thus, antioxidant supple-
mentation needs to be evaluated on a

Cancer Cell 37, February 10, 2020 ª 2020 Elsevier Inc. 141

Figure 1. Cheung and Colleagues Discover a New Concept in which ROS Play a Dynamic Role in Pancreatic Cancer Development
In early stages of cancer, high TIGAR levels decrease ROS to promote cancer initiation. At later stages, low TIGAR levels increase ROS to support metastasis.
Cancer cells in the metastatic niche may increase TIGAR expression to potentially drive proliferation.
personalized level in the treatment of can-
cer progression, and further work is
required to fully reveal the multifaceted
role of ROS in cancer, metastasis, and
therapy.
ACKNOWLEDGMENTS
S-MF acknowledges funding from the European
Research Council under the ERC Consolidator
Grant Agreement n. 771486–MetaRegulation,
FWO – Research Grants and Projects
(G088318N, G098120N), and KU Leuven – Methu-
salem Co-Funding. SYL acknowledges funding
from the National Science Foundation under
CAREER Grant No. (CBET 1845006), METAvivor
Early Career Investigator Grant, and AACR-Incyte
Corporation NextGen Grant for Transformative
Cancer Research, Grant Number 16-20-46-
LUNT. We would like to acknowledge http://
www.somersault1824.com/ for image elements
used in the figures (Creative Commons license
CC BY-NC-SA 4.0).
DECLARATION OF INTERESTS
S.-M.F. has received funding from Bayer, Merck,
and BlackBelt Therapeutics.
142 Cancer Cell 37, February 10, 2020
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