Accurate determination of CRISPR-mediated gene fitness in transplantable tumours

Peter Eirew, Ciara O’Flanagan, Jerome Ting, Sohrab Salehi, Jazmine Brimhall, Beixi Wang, Justina Biele, Teresa Algara, So Ra Lee, Corey Hoang, Damian Yap, Steven McKinney, Cherie Bates, Esther Kong, Daniel Lai, Sean Beatty, Mirela Andronescu, Elena Zaikova, Tyler Funnell, Nicholas Ceglia, Stephen Chia, Karen Gelmon, Colin Mar, Sohrab Shah, Andrew Roth, Alexandre Bouchard-Côté () and Samuel Aparicio ()
Additional contact information
Peter Eirew: BC Cancer
Ciara O’Flanagan: BC Cancer
Jerome Ting: BC Cancer
Sohrab Salehi: BC Cancer
Jazmine Brimhall: BC Cancer
Beixi Wang: BC Cancer
Justina Biele: BC Cancer
Teresa Algara: BC Cancer
So Ra Lee: BC Cancer
Corey Hoang: BC Cancer
Damian Yap: BC Cancer
Steven McKinney: BC Cancer
Cherie Bates: BC Cancer
Esther Kong: BC Cancer
Daniel Lai: BC Cancer
Sean Beatty: BC Cancer
Mirela Andronescu: BC Cancer
Elena Zaikova: BC Cancer
Tyler Funnell: Memorial Sloan Kettering Cancer Center
Nicholas Ceglia: Memorial Sloan Kettering Cancer Center
Stephen Chia: BC Cancer
Karen Gelmon: BC Cancer
Colin Mar: BC Cancer
Sohrab Shah: Memorial Sloan Kettering Cancer Center
Andrew Roth: BC Cancer
Alexandre Bouchard-Côté: University of British Columbia
Samuel Aparicio: BC Cancer

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Assessing tumour gene fitness in physiologically-relevant model systems is challenging due to biological features of in vivo tumour regeneration, including extreme variations in single cell lineage progeny. Here we develop a reproducible, quantitative approach to pooled genetic perturbation in patient-derived xenografts (PDXs), by encoding single cell output from transplanted CRISPR-transduced cells in combination with a Bayesian hierarchical model. We apply this to 181 PDX transplants from 21 breast cancer patients. We show that uncertainty in fitness estimates depends critically on the number of transplant cell clones and the variability in clone sizes. We use a pathway-directed allelic series to characterize Notch signaling, and quantify TP53 / MDM2 drug-gene conditional fitness in outlier patients. We show that fitness outlier identification can be mirrored by pharmacological perturbation. Overall, we demonstrate that the gene fitness landscape in breast PDXs is dominated by inter-patient differences.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31830-2

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DOI: 10.1038/s41467-022-31830-2

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