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Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer

  1. Yusuke Inoue
  2. Ana Nikolic
  3. Dylan Farnsworth
  4. Rocky Shi
  5. Fraser D Johnson
  6. Alvin Liu
  7. Marc Ladanyi
  8. Romel Somwar
  9. Marco Gallo
  10. William W Lockwood  Is a corresponding author
  1. British Columbia Cancer Agency, Canada
  2. University of Calgary, Canada
  3. Memorial Sloan-Kettering Cancer Center, United States
Research Article
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Cite this article as: eLife 2021;10:e66524 doi: 10.7554/eLife.66524

Abstract

Lineage transformation between lung cancer subtypes is a poorly understood phenomenon associated with resistance to treatment and poor patient outcomes. Here, we aimed to model this transition to define underlying biological mechanisms and identify potential avenues for therapeutic intervention. Small cell lung cancer (SCLC) is neuroendocrine in identity and, in contrast to non-SCLC (NSCLC), rarely contains mutations that drive the MAPK pathway. Likewise, NSCLCs that transform to SCLC concomitantly with development of therapy resistance downregulate MAPK signaling, suggesting an inverse relationship between pathway activation and lineage state. To test this, we activated MAPK in SCLC through conditional expression of mutant KRAS or EGFR, which revealed suppression of the neuroendocrine differentiation program via ERK. We found that ERK induces the expression of ETS factors that mediate transformation into a NSCLC-like state. ATAC-seq demonstrated ERK-driven changes in chromatin accessibility at putative regulatory regions and global chromatin rewiring at neuroendocrine and ETS transcriptional targets. Further, ERK-mediated induction of ETS factors as well as suppression of neuroendocrine differentiation were dependent on histone acetyltransferase activities of CBP/p300. Overall, we describe how the ERK-CBP/p300-ETS axis promotes a lineage shift between neuroendocrine and non-neuroendocrine lung cancer phenotypes and provide rationale for the disruption of this program during transformation-driven resistance to targeted therapy.

Data availability

Gene expression data has been deposited to GEO under the accession code GSE160482. ATAC seq data has been deposited to GEO under the accession code GSE160204

The following data sets were generated

Article and author information

Author details

  1. Yusuke Inoue

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8075-0597
  2. Ana Nikolic

    Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Dylan Farnsworth

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2402-159X
  4. Rocky Shi

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Fraser D Johnson

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Alvin Liu

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Marc Ladanyi

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Romel Somwar

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Marco Gallo

    Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. William W Lockwood

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    For correspondence
    wlockwood@bccrc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9831-3408

Funding

Canadian Institutes of Health Research (PJT-148725)

  • William W Lockwood

Michael Smith Foundation for Health Research (Scholar Award)

  • William W Lockwood

Canadian Institutes of Health Research (New Investigator Award)

  • William W Lockwood

British Columbia Lung Association (Research Grant)

  • Yusuke Inoue
  • William W Lockwood

Terry Fox Research Institute (New Investigator Award)

  • William W Lockwood

Canadian Institutes of Health Research (PJT-156278)

  • Marco Gallo

Canada Research Chairs (Brain Cancer Epigenomics (Tier 2))

  • Marco Gallo

Alberta Health Services (Clinician Investigator Program fellowship)

  • Ana Nikolic

Alberta Innovates (Fellowship)

  • Ana Nikolic

Japanese Respiratory Society (Lilly Oncology Fellowship Program Award)

  • Yusuke Inoue

Michael Smith Foundation for Health Research (Fellowship)

  • Yusuke Inoue

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Maureen E Murphy, The Wistar Institute, United States

Publication history

  1. Received: January 13, 2021
  2. Accepted: June 11, 2021
  3. Accepted Manuscript published: June 14, 2021 (version 1)
  4. Accepted Manuscript updated: June 18, 2021 (version 2)
  5. Version of Record published: August 4, 2021 (version 3)

Copyright

© 2021, Inoue 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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