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

  1. Debjani Pal
  2. Anja Pertot
  3. Nitin H Shirole
  4. Zhan Yao
  5. Naishitha Anaparthy
  6. Tyler Garvin
  7. Hilary Cox
  8. Kenneth Chang
  9. Fred Rollins
  10. Jude Kendall
  11. Leyla Edwards
  12. Vijay A. Singh
  13. Gary C. Stone
  14. Michael C. Schatz
  15. James Hicks
  16. Gregory Hannon
  17. Raffaella Sordella  Is a corresponding author
  1. Cold Spring Harbor Laboratory, United States
  2. Huntington Hospital, Northwell Health, United States
  3. Cold Spring Harbor Laboratory/ Johns Hopkins University, United States
  4. Cold Spring Harbor Laboratory/ University of Southern California, United States
  5. 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

The following previously published data sets were used

Article and author information

Author details

  1. Debjani Pal

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anja Pertot

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nitin H Shirole

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhan Yao

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Naishitha Anaparthy

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tyler Garvin

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hilary Cox

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Kenneth Chang

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Fred Rollins

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jude Kendall

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Leyla Edwards

    Pathology, Huntington Hospital, Northwell Health, Huntington, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Vijay A. Singh

    Pathology, Huntington Hospital, Northwell Health, Huntington, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Gary C. Stone

    Pathology, Huntington Hospital, Northwell Health, Huntington, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Michael C. Schatz

    Quantitative Biology, Cold Spring Harbor Laboratory/ Johns Hopkins University, Cold Spring Harbor/ Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. James Hicks

    Quantitative Biology, Cold Spring Harbor Laboratory/ University of Southern California, Cold Spring Harbor/ Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Gregory Hannon

    cruk cambridge insititue, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Raffaella Sordella

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    For correspondence
    sordella@cshl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9745-1227

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

  1. 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

  1. Received: September 17, 2016
  2. Accepted: January 14, 2017
  3. Accepted Manuscript published: January 16, 2017 (version 1)
  4. 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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  1. Debjani Pal
  2. Anja Pertot
  3. Nitin H Shirole
  4. Zhan Yao
  5. Naishitha Anaparthy
  6. Tyler Garvin
  7. Hilary Cox
  8. Kenneth Chang
  9. Fred Rollins
  10. Jude Kendall
  11. Leyla Edwards
  12. Vijay A. Singh
  13. Gary C. Stone
  14. Michael C. Schatz
  15. James Hicks
  16. Gregory Hannon
  17. Raffaella Sordella
(2017)
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

Share this article

https://doi.org/10.7554/eLife.21615

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