TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells
- Cold Spring Harbor Laboratory, United States
- Huntington Hospital, Northwell Health, United States
- Cold Spring Harbor Laboratory/ Johns Hopkins University, United States
- Cold Spring Harbor Laboratory/ University of Southern California, United States
- University of Cambridge, United Kingdom
Abstract
Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24- cell surface marker profile. Here, we report that human CD44+/CD24- cancer cells are genetically highly unstable due to intrinsic defects in their DNA repair capabilities. In fact, in CD44+/CD24- cells constitutive activation of the TGF-beta axis was both necessary and sufficient to reduce the expression of genes that are critical in coordinating DNA damage repair mechanisms. Consequently, we observed that cancer cells that reside in a CD44+/CD24- state are characterized by increased accumulation of DNA copy number alterations, greater genetic diversity and improved adaptability to drug treatment. Together, these data suggest that the transition into a CD44+/CD24- cell state can promote intra-tumor genetic heterogeneity, spur tumor evolution and increase tumor fitness.
Data availability
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The Cancer Genome Atlas Pan-Cancer analysis projectPublicly available at Gitools (http://www.gitools.org).
Article and author information
Author details
Raffaella Sordella
Funding
National Cancer Institute (NCI P01 CA129243-06)
- Raffaella Sordella
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Rik Derynck, University of California, San Francisco, United States
Ethics
Human subjects: Informed consent was received from all patients who participated in the study 14-496 (PI V Singh) .
Version history
- Received: September 17, 2016
- Accepted: January 14, 2017
- Accepted Manuscript published: January 16, 2017 (version 1)
- Version of Record published: March 10, 2017 (version 2)
Copyright
© 2017, Pal et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells
eLife 6:e21615.
https://doi.org/10.7554/eLife.21615
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