PONE-D-25-14812STAG2 mutations in the normal colon induce upregulation of oncogenic pathways in neighbouring wildtype cellsPLOS ONE

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: 1. The hypothesis that STAG2 mutations affect neighboring wildtype cells via non-cell-autonomous mechanisms is interesting, and the approach is suitable.

2. The connection to CRC is tenuous, and will necessitate functional verification (e.g., tumorigenicity assays).

3. Inclusion of APC mutants as positive controls is commendable. However, co-culture conditions and proportions of mutant:wildtype cells should be quantitatively detailed.

4. Current interpretation is speculative; prioritize elucidating definitive molecular mechanisms.

5. Provide a summary schematic describing the proposed mechanism in this study to enhance the understanding.

Reviewer #2: The authors have revealed that STAG2 mutations in normal colon organoids upregulates the expression of key oncogenic pathways in neighboring cells not bearing STAG3 mutations. This is a very interesting and timely paper. I have no comments on this well-written, intriguing paper other than further information is needed in the Discussion describing potential mechanisms (exosomes for example) and the fact that it is known and numerous papers in the literature demonstrating that mutations in stroma, namely fibroblasts, can activate pro-proliferative and oncogenic pathways in neighboring epithelia.

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Reviewer #1: No

Reviewer #2: No

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STAG2 mutations in the normal colon induce upregulation of oncogenic pathways in neighbouring wildtype cells

PONE-D-25-14812R1

Dear Dr. Chan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Xinjun Lu

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewer #1:

Reviewer #2:

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have satisfactorily addressed the previous reviewer comments, and the manuscript is technically sound with data that support the conclusions.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #2: No

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