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Sialic acid metabolism: a key player in breast cancer metastasis

revealed by metabolomics
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Shao Thing Teoh, Martin Ogrodzinski, Christina Ross, Kent Hunter and Sophia Y Lunt*
Original Research, Front. Oncol. - Molecular and Cellular Oncology
Supplementary materials
Submitted on: 06 Feb 2018, Edited by: Thomas G P Grünewald
Manuscript ID: 360894
Research Topic: Cancer – A Spectrum of Diseases at the Crossroad Between Cell Signaling, View submitted files history
(Epi)genetics, and the Microenvironment
Keywords: breast cancer, metastasis, Metabolism, Metabolomics, sialic acid, Mass
Spectrometry, mouse models, CMAS, …
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Reviewer 1
Independent review report submitted: 21 Feb 2018
Interactive review activated: 02 Mar 2018

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 EVALUATION

Q 1 Please summarize the main findings of the study.

Reviewer
  1 | 21 Feb 2018 | 12:37 #1

see 4

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Q 2 Please highlight the limitations and strengths of the study.

Reviewer
  1 | 21 Feb 2018 | 12:37 #1

see 4

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 Q 3 Are there objective errors in the methods or results, and are the conclusions
supported by the presented data?

No answer given.

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Q 4 Please provide your detailed review report to the authors:

(annotated pdfs can be sent to the Editorial Office via email)

Reviewer
  1 | 21 Feb 2018 | 12:37 #1

Reviewer Comments on ID: 360894

Teoh and colleagues applied metabolomics to assess the metabolism of poorly versus highly
metastastic mouse breast cancer cells. Their data reveal that highly metastatic breast
cancer cells have a higher flux through the sialic acid biosynthesis pathway compared with
less metastatic cells. Using CMAS knockout lines, they showed that CMP-sialic acid
production is indeed essential for metastasis. Altogether, Teoh and colleagues provide sound
experimental evidence linking the metabolic flux through the sialic acid pathway with the
metastatic potential of murine breast cancer cell lines. Although earlier studies already
demonstrated a link between sialic acid and metastasis, the present study is complemetary
in that it uses a metabolomics approach to measure the flux in sialic acid biosynthesis and
confirms the outcome at the functional level.
Overall the manuscript is well-written and the experiments support the conclusions drawn.
This study is a nice example of using an unbiased method such as metabolomics to identify
factors involved in metastatic disease. However, the manuscript could be improved by
addressing the following issues:

Main comments:
− Sialic acids are a family of various neuraminic acid derivatives. The authors should specify
which (CMP)-sialic acid type was measured (Neu5Gc, Neu5Ac etc.)? Regarding the study has
been performed in mice, which sialic acid type was most abundant and were there any
differences in the usage of the sialic acid types between the poorly and highly metastatic
tumors?
− How does the enhanced metabolic flux through the sialic acid pathway in the metastatic
cells relate to differences in endogenous expression of genes involved in sialic acid
biosynthesis? For instance by comparing basal expression levels of GFPT1, PGM3, GNE, CMAS,
SLC35A1 etc. between the 4T1, 4T07 and 67NR lines e.g. by qPCR or western blot?

Minor comments:
− Do the differences in intracellular sialic acid concentrations correlate with sialoglycan
expression at the cell membrane? This has been suggested by the work of Miyahara (Angew
Chem Int Ed Engl. 2010, J Am Chem Soc. 2009) and others.
− Figure 5. It is difficult to discriminate the blue lines for 4T07 and 67N, please consider
using different colors or symbols.
− p. 11. ll. 1-2: This points to sialyltransferases as another possible target for inhibiting
metastasis through disrupting cell surface sialylation. Several studies have shown that
sialyltransferase expression correlates with a metastatic tumor phenotype and that blocking
sialyltransferases inhibits metastatic spread and should be referenced here (Julien S et al
2011 Canc. Res. 71(24). Perez-Garay et al 2010 Plos One e12524, Bull et al 2015 ACS Nano
9(11)).
− The discussion section is mainly a summary of related studies rather than a discussion of
the presented results. The discussion could be improved if the authors would place their
results more central and relate their data for example to the papers mentioned above.
− Supplementary figure 2, upper panel: Why is there no band detectable for vinculin in the
WT lane?

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Q 5 Check List

Reviewer
  1 | 21 Feb 2018 | 12:37 #1

Is the English language adequate?

- Yes
 Is the quality of the figures and tables satisfactory?
- Yes

Does the reference list cover the relevant literature adequately and in an objective manner?
- No

Are the statistical methods valid and correctly applied? (e.g. sample size, choice of test)
- Yes

Are the methods sufficiently documented to allow replication studies?

- Yes

Are the data underlying the study available in either the article, supplement, or deposited
in a repository?
- Yes

Does the study adhere to ethical standards including ethics committee approval and consent
procedure?
- Yes

Have standard biosecurity and institutional safety procedures been adhered to?
- Yes

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 QUALITY ASSESSMENT

Q 6 Originality of study

Q 7 Rigor of the study

Q 8 Significance of study to the field

Q 9 Interest of study to a general audience

Q 10 Quality of writing

 REVISION LEVEL

Q 11 What is the level of revision required based on your comments:

Reviewer
  1 | 21 Feb 2018 | 12:37 #1

Moderate revisions

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