Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway
- Cancer Research Malaysia, Malaysia
- Wellcome Trust Sanger Institute, United Kingdom
- Wellcome Trust Genome Campus, United Kingdom
- Moffitt Cancer Center, United States
- 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).
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Genome-wide CRISPR screens reveal fitness genes in the Hippo pathway for oral squamous cell carcinomaFigshare, doi:10.6084/m9.figshare.11919753.
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Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)cbioportal, doi:10.1038/nature14129.
Article and author information
Author details
Annie Wai Yeeng Chai
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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