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.
Reviewing Editor
- Erica A Golemis, Fox Chase Cancer Center, United States
Version history
- Received: April 10, 2020
- Accepted: September 28, 2020
- Accepted Manuscript published: September 29, 2020 (version 1)
- Version of Record published: October 27, 2020 (version 2)
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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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
Further reading
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- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
