1. Cancer Biology
  2. Cell Biology
Download icon

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
Research Article
  • Cited 9
  • Views 2,920
  • Annotations
Cite this article as: eLife 2017;6:e21615 doi: 10.7554/eLife.21615

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.

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.

Ethics

Human subjects: Informed consent was received from all patients who participated in the study 14-496 (PI V Singh) .

Reviewing Editor

  1. Rik Derynck, University of California, San Francisco, United States

Publication 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.

Metrics

  • 2,920
    Page views
  • 677
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Scopus, Crossref.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Cancer Biology
    Allison N Lau et al.
    Research Article Updated

    Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.

    1. Cancer Biology
    2. Immunology and Inflammation
    Biancamaria Ricci et al.
    Research Article

    Cancer-associated fibroblasts (CAFs) are a heterogeneous population of mesenchymal cells supporting tumor progression, whose origin remains to be fully elucidated. Osterix (Osx) is a marker of osteogenic differentiation, expressed in skeletal progenitor stem cells and bone-forming osteoblasts. We report Osx expression in CAFs and by using Osx-cre;TdTomato reporter mice we confirm the presence and pro-tumorigenic function of TdTOSX+ cells in extra-skeletal tumors. Surprisingly, only a minority of TdTOSX+ cells expresses fibroblast and osteogenic markers. The majority of TdTOSX+ cells express the hematopoietic marker CD45, have a genetic and phenotypic profile resembling that of tumor infiltrating myeloid and lymphoid populations, but with higher expression of lymphocytic immune suppressive genes. We find Osx transcript and Osx protein expression early during hematopoiesis, in subsets of hematopoietic stem cells and multipotent progenitor populations. Our results indicate that Osx marks distinct tumor promoting CD45- and CD45+ populations and challenge the dogma that Osx is expressed exclusively in cells of mesenchymal origin.