1. Cancer Biology

NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma

  1. Ganapati V Hegde  Is a corresponding author
  2. Cecile de la Cruz
  3. Jennifer M Giltnane
  4. Lisa Crocker
  5. Avinashnarayan Venkatanarayan
  6. Gabriele Schaefer
  7. Debra Dunlap
  8. Joerg D Hoeck
  9. Robert Piskol
  10. Florian Gnad
  11. Zora Modrusan
  12. Frederic J de Sauvage
  13. Christian W Siebel
  14. Erica L Jackson  Is a corresponding author
  1. Genentech Inc, United States
https://doi.org/10.7554/eLife.46551
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  1. Ganapati V Hegde
  2. Cecile de la Cruz
  3. Jennifer M Giltnane
  4. Lisa Crocker
  5. Avinashnarayan Venkatanarayan
  6. Gabriele Schaefer
  7. Debra Dunlap
  8. Joerg D Hoeck
  9. Robert Piskol
  10. Florian Gnad
  11. Zora Modrusan
  12. Frederic J de Sauvage
  13. Christian W Siebel
  14. Erica L Jackson
(2019)
NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
eLife 8:e46551.
https://doi.org/10.7554/eLife.46551
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Abstract

Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to target TP63 or it's downstream effectors. In this study we demonstrate that TP63 directly regulates NRG1 expression in human SCC cell lines and that NRG1 is a critical component of the TP63 transcriptional program. Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth. Together, our findings identify a lineage-specific function of NRG1 in SCCs of diverse anatomic origin.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data file has been provided for Figure 4.

Article and author information

Author details

  1. Ganapati V Hegde

    Discovery Oncology, Genentech Inc, South San Francisco, United States
    For correspondence
    gvhegde@gmail.com
    Competing interests
    Ganapati V Hegde, employee of Genentech Inc at the time of participation in this study.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6473-153X

  2. Cecile de la Cruz

    Translational Oncology, Genentech Inc, South San Francisco, United States
    Competing interests
    Cecile de la Cruz, employee of Genentech Inc at the time of participation in this study.

  3. Jennifer M Giltnane

    Department of Pathology, Genentech Inc, South San Francisco, United States
    Competing interests
    Jennifer M Giltnane, employee of Genentech Inc at the time of participation in this study.

  4. Lisa Crocker

    Translational Oncology, Genentech Inc, South San Francisco, United States
    Competing interests
    Lisa Crocker, employee of Genentech Inc at the time of participation in this study.

  5. Avinashnarayan Venkatanarayan

    Discovery Oncology, Genentech Inc, South San Francisco, United States
    Competing interests
    Avinashnarayan Venkatanarayan, employee of Genentech Inc at the time of participation in this study.

  6. Gabriele Schaefer

    Translational Oncology, Genentech Inc, South San Francisco, United States
    Competing interests
    Gabriele Schaefer, employee of Genentech Inc at the time of participation in this study.

  7. Debra Dunlap

    Pathology, Genentech Inc, South San Francisco, United States
    Competing interests
    Debra Dunlap, employee of Genentech Inc at the time of participation in this study.

  8. Joerg D Hoeck

    Molecular Oncology, Genentech Inc, South San Francisco, United States
    Competing interests
    Joerg D Hoeck, employee of Genentech Inc at the time of participation in this study.

  9. Robert Piskol

    Bioinformatics, Genentech Inc, South San Francisco, United States
    Competing interests
    Robert Piskol, employee of Genentech Inc at the time of participation in this study.

  10. Florian Gnad

    Bioinformatics, Genentech Inc, South San Francisco, United States
    Competing interests
    Florian Gnad, employee of Genentech Inc at the time of participation in this study.

  11. Zora Modrusan

    Department of Molecular Biology, Genentech Inc, South San Francisco, United States
    Competing interests
    Zora Modrusan, employee of Genentech Inc at the time of participation in this study.

  12. Frederic J de Sauvage

    Department of Molecular Biology, Genentech Inc, South San Francisco, United States
    Competing interests
    Frederic J de Sauvage, employee of Genentech Inc at the time of participation in this study.

  13. Christian W Siebel

    Discovery Oncology, Genentech Inc, South San Francisco, United States
    Competing interests
    Christian W Siebel, employee of Genentech Inc at the time of participation in this study.

  14. Erica L Jackson

    Discovery Oncology, Genentech Inc, South San Francisco, United States
    For correspondence
    ericajackso@gmail.com
    Competing interests
    Erica L Jackson, employee of Genentech Inc at the time of participation in this study.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7100-8021

Funding

The authors declare that there was no funding for this work

Reviewing Editor

  1. William C Hahn, Dana-Farber Cancer Institue, United States

Ethics

Animal experimentation: All animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) at Genentech. The animal studies included herein were performed based on approved IACUC protocol numbers (LASAR 10-2319A, 16-1304, 16-1304A, 16-0098, 16-1120, 16-1143 and 16-2005, 16-1120).

Version history

  1. Received: March 4, 2019
  2. Accepted: May 28, 2019
  3. Accepted Manuscript published: May 30, 2019 (version 1)
  4. Version of Record published: July 2, 2019 (version 2)

Copyright

© 2019, Hegde 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. Ganapati V Hegde
  2. Cecile de la Cruz
  3. Jennifer M Giltnane
  4. Lisa Crocker
  5. Avinashnarayan Venkatanarayan
  6. Gabriele Schaefer
  7. Debra Dunlap
  8. Joerg D Hoeck
  9. Robert Piskol
  10. Florian Gnad
  11. Zora Modrusan
  12. Frederic J de Sauvage
  13. Christian W Siebel
  14. Erica L Jackson
(2019)
NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
eLife 8:e46551.
https://doi.org/10.7554/eLife.46551

Share this article

https://doi.org/10.7554/eLife.46551

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