Decision letter | TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24− cancer cells

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TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24− cancer cells

Decision letter

Affiliation details

Cold Spring Harbor Laboratory, United States; Stony Brook University, United States; Huntington Hospital, Northwell Health, United States; University of Southern California, United States; Cancer Research UK – Cambridge Institute, University of Cambridge, United Kingdom
Rik Derynck, Reviewing editor, University of California, San Francisco, United States

In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.

Thank you for submitting your article "TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cells" for consideration by eLife. Your article has been favorably evaluated by Kevin Struhl (Senior Editor) and three reviewers, one of whom is a member of our Board of Reviewing Editors. The reviewers have opted to remain anonymous.

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

As you will see from the reviewers' reports, there are differing opinions to what extent this manuscript presents substantial novelty, in how far the previous literature has been properly credited, and in how far this is a logical extension of previous research by your lab and other labs. In fact, this manuscript is presented as if all findings are new, and only in the second to last paragraph are previous observations mentioned "in passing". While we appreciate the logical flow of the experiments and how you came to the important conclusions based on the data provided, the manuscript would come over much better if you present right upfront what has already been learnt from previous publications, so that you and the reader can then better appreciate the novelty. This relates to previous relevant observations linking e.g. TGF-b signaling to increased chemoresistance, or TGF-b signaling to impaired DNA repair, or CSCs to DNA repair, etc. We do, however, fully appreciate the overall novelty and importance.

There were also comments that need to be experimentally addressed. Specifically:

It feels somewhat uncomfortable using only LY2157299 as TGF-b inhibitor, since it does have other signaling kinase targets besides the type I TGF-b receptor. Considering the central role of this aspect in the manuscript, further validation using another (more specific) TGF-b signaling inhibitor or neutralizing TGF-b antibodies would help. Even though LY2157299 is clinically under evaluation as galunisertib, further substantiation of specific TGF-b signaling would provide confidence.

The DR-GFP reporter system is used in U2OS cells (Figure 4I and supplementary data). These cells are not used in other experiments with major findings in this manuscript, are from mesenchymal origin, whereas the others are carcinomas, and have impaired TGF-b signaling. It would provide confidence to have this assay done in H1650 cells.

Additional comments to be addressed are:

The title and/or Abstract should provide a clear indication of the biological system under investigation (i.e., species name or broader taxonomic group, if appropriate). Please revise your title and/or Abstract with this advice in mind.

In all figures, please explain the error bars – what do they represent and if variance, how many experiments. Are the ones on the data from two experiments a range?

Throughout the paper where CNAs are discussed, please do not refer to "DNA breaks" or "break points". What is being quantifying is novel DNA junctions or join points. "Breaks" implies a mechanism of genome rearrangement that the authors do not know has occurred-one using DNA breakage. Models like microhomology-mediated replicative template switching and MMBIR are dominating modern understanding of CNA formation, and these are not break and join models. I suggest adopting either "join points" or new "DNA junctions", defining it for readers, and using throughout in all.