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Molecular Cancer Research
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Cell Fate Decisions

Aberrant Induction of a Mesenchymal/Stem Cell Program Engages Senescence in Normal Mammary Epithelial Cells

Benjamin L. Bryson, Ilaria Tamagno, Sarah E. Taylor, Neetha Parameswaran, Noah M. Chernosky, Nikhila Balasubramaniam and Mark W. Jackson
Benjamin L. Bryson
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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  • ORCID record for Benjamin L. Bryson
Ilaria Tamagno
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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Sarah E. Taylor
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
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Neetha Parameswaran
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
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Noah M. Chernosky
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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Nikhila Balasubramaniam
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
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Mark W. Jackson
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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  • For correspondence: mwj7@cwru.edu
DOI: 10.1158/1541-7786.MCR-19-1181 Published April 2021
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Abstract

Although frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine, oncostatin M, activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and requires cooperation between STAT3 and the TGFβ effector, SMAD3. Importantly, as cells escape CIS, they retain the mesenchymal/SC program and are thereby bestowed with a set of cancer SC (CSC) traits. Of therapeutic importance, cells that escape CIS can be induced back into senescence by CDK4/6 inhibition, confirming that the mechanisms allowing cells to escape senescence are targetable and reversible. Moreover, by combining CDK4/6 inhibition with a senolytic therapy, mesenchymal/CSCs can be efficiently killed. Our studies provide insight into how the CIS barriers that prevent tumorigenesis can be exploited as potential therapies for highly aggressive cancers.

Implications: These studies reveal how a normal cell's arduous escape from senescence can bestow aggressive features early in the transformation process, and how this persistent mesenchymal/SC program can create a novel potential targetability following tumor development.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:651–66

  • Received December 9, 2019.
  • Revision received October 23, 2020.
  • Accepted December 15, 2020.
  • Published first December 22, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (4)
April 2021
Volume 19, Issue 4
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Aberrant Induction of a Mesenchymal/Stem Cell Program Engages Senescence in Normal Mammary Epithelial Cells
Benjamin L. Bryson, Ilaria Tamagno, Sarah E. Taylor, Neetha Parameswaran, Noah M. Chernosky, Nikhila Balasubramaniam and Mark W. Jackson
Mol Cancer Res April 1 2021 (19) (4) 651-666; DOI: 10.1158/1541-7786.MCR-19-1181

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Aberrant Induction of a Mesenchymal/Stem Cell Program Engages Senescence in Normal Mammary Epithelial Cells
Benjamin L. Bryson, Ilaria Tamagno, Sarah E. Taylor, Neetha Parameswaran, Noah M. Chernosky, Nikhila Balasubramaniam and Mark W. Jackson
Mol Cancer Res April 1 2021 (19) (4) 651-666; DOI: 10.1158/1541-7786.MCR-19-1181
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