Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

  1. Annie Wai Yeeng Chai
  2. Pei San Yee
  3. Stacey Price
  4. Shi Mun Yee
  5. Hui Mei Lee
  6. Vivian KH Tiong
  7. Emanuel Gonçalves
  8. Fiona M Behan
  9. Jessica Bateson
  10. James Gilbert
  11. Aik Choon Tan
  12. Ultan McDermott
  13. Mathew J Garnett
  14. Sok Ching Cheong  Is a corresponding author
  1. Cancer Research Malaysia, Malaysia
  2. Wellcome Trust Sanger Institute, United Kingdom
  3. Wellcome Trust Genome Campus, United Kingdom
  4. Moffitt Cancer Center, United States
  5. AstraZeneca, United Kingdom

Abstract

New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identified OSCC-related cancer genes are non-essential and could have limited therapeutic value, while other fitness genes warrant further investigation for their potential as therapeutic targets. We validate a distinctive dependency on YAP1 and WWTR1 of the Hippo pathway, where the lost-of-fitness effect of one paralog can be compensated only in a subset of lines. We also discover that OSCCs with WWTR1 dependency signature are significantly associated with biomarkers of favourable response towards immunotherapy. In summary, we have delineated the genetic vulnerabilities of OSCC, enabling the prioritization of therapeutic targets for further exploration, including the targeting of YAP1 and WWTR1.

Data availability

All main data generated or analysed during this study are included in the manuscript and supplementary files. Source data files for each figures and supplements have also been provided.The larger datasets of CRISPR screens, WES and RNA-sequencing output are available from Figshare (https://doi.org/10.6084/m9.figshare.11919753).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Annie Wai Yeeng Chai

    Head and Neck Cancer Research Team, Cancer Research Malaysia, Subang Jaya, Malaysia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8015-6050
  2. Pei San Yee

    Head and Neck Cancer Research Team, Cancer Research Malaysia, Subang Jaya, Malaysia
    Competing interests
    The authors declare that no competing interests exist.
  3. Stacey Price

    Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Shi Mun Yee

    Head and Neck Cancer Research Team, Cancer Research Malaysia, Subang Jaya, Malaysia
    Competing interests
    The authors declare that no competing interests exist.
  5. Hui Mei Lee

    Head and Neck Cancer Research Team, Cancer Research Malaysia, Subang Jaya, Malaysia
    Competing interests
    The authors declare that no competing interests exist.
  6. Vivian KH Tiong

    Head and Neck Cancer Research Team, Cancer Research Malaysia, Subang Jaya, Malaysia
    Competing interests
    The authors declare that no competing interests exist.
  7. Emanuel Gonçalves

    Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9967-5205
  8. Fiona M Behan

    Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Jessica Bateson

    Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. James Gilbert

    Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Aik Choon Tan

    Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Ultan McDermott

    Oncology R&D, AstraZeneca, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Mathew J Garnett

    Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Sok Ching Cheong

    Head and Neck Cancer Research Team, Cancer Research Malaysia, Subang Jaya, Malaysia
    For correspondence
    sokching.cheong@cancerresearch.my
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6765-9542

Funding

Medical Research Council (MR/P013457/1)

  • Ultan McDermott
  • Mathew J Garnett
  • Sok Ching Cheong

Wellcome Trust (206194)

  • Stacey Price
  • Emanuel Gonçalves
  • Fiona M Behan
  • Jessica Bateson
  • James Gilbert
  • Mathew J Garnett

Cancer Research Malaysia (-)

  • Annie Wai Yeeng Chai
  • Pei San Yee
  • Shi Mun Yee
  • Hui Mei Lee
  • Vivian KH Tiong
  • Sok Ching Cheong

This work was directly supported by the Newton-Ungku Omar Fund and the Medical Research Council, United Kingdom (MR/P013457/1). Authors in S.C.C.'s group were supported by sponsors of Cancer Research Malaysia; Authors in M.J.G's group were supported by Wellcome. Other funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Chai 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. Annie Wai Yeeng Chai
  2. Pei San Yee
  3. Stacey Price
  4. Shi Mun Yee
  5. Hui Mei Lee
  6. Vivian KH Tiong
  7. Emanuel Gonçalves
  8. Fiona M Behan
  9. Jessica Bateson
  10. James Gilbert
  11. Aik Choon Tan
  12. Ultan McDermott
  13. Mathew J Garnett
  14. Sok Ching Cheong
(2020)
Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway
eLife 9:e57761.
https://doi.org/10.7554/eLife.57761

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https://doi.org/10.7554/eLife.57761