Accurate determination of CRISPR-mediated gene fitness in transplantable tumours Journal Article

   

Authors:	Eirew, P.; O’Flanagan, C.; Ting, J.; Salehi, S.; Brimhall, J.; Wang, B.; Biele, J.; Algara, T.; Lee, S. R.; Hoang, C.; Yap, D.; McKinney, S.; Bates, C.; Kong, E.; Lai, D.; Beatty, S.; Andronescu, M.; Zaikova, E.; Funnell, T.; Ceglia, N.; Chia, S.; Gelmon, K.; Mar, C.; Shah, S.; Roth, A.; Bouchard-Côté, A.; Aparicio, S.
Article Title:	Accurate determination of CRISPR-mediated gene fitness in transplantable tumours
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. © 2022, The Author(s).
Keywords:	gene; fitness; tumor; cell; cancer
Journal Title:	Nature Communications
Volume:	13
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2022-08-04
Start Page:	4534
Language:	English
DOI:	10.1038/s41467-022-31830-2
PUBMED:	35927228
PROVIDER:	scopus
PMCID:	PMC9352714
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85135426762&doi=10.1038%2fs41467-022-31830-2&partnerID=40&md5=9aea1ed9868ee595e709dfebdd3b0068
Notes:	Article -- Export Date: 1 September 2022 -- Source: Scopus

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