Accurate determination of CRISPR-mediated gene fitness in transplantable tumours

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 patie...

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Vydáno v:	Nature communications Ročník 13; číslo 1; s. 4534 - 19
Hlavní autoři:	Eirew, Peter, O’Flanagan, Ciara, Ting, Jerome, Salehi, Sohrab, Brimhall, Jazmine, Wang, Beixi, Biele, Justina, Algara, Teresa, Lee, So Ra, Hoang, Corey, Yap, Damian, McKinney, Steven, Bates, Cherie, Kong, Esther, Lai, Daniel, Beatty, Sean, Andronescu, Mirela, Zaikova, Elena, Funnell, Tyler, Ceglia, Nicholas, Chia, Stephen, Gelmon, Karen, Mar, Colin, Shah, Sohrab, Roth, Andrew, Bouchard-Côté, Alexandre, Aparicio, Samuel
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 04.08.2022 Nature Publishing Group Nature Portfolio
Témata:	13/44 42/109 42/47 45/23 49/109 631/154/556 631/67/1347 631/67/2329 631/67/69 64/60 Animals Bayes Theorem Bayesian analysis Breast cancer Breast Neoplasms - genetics Cell lineage Clustered Regularly Interspaced Short Palindromic Repeats CRISPR Data analysis Disease Models, Animal Female Fitness Heterografts Humanities and Social Sciences Humans In vivo methods and tests Mathematical models MDM2 protein multidisciplinary Outliers (statistics) p53 Protein Perturbation Progeny Reproductive fitness Science Science (multidisciplinary) Transplants Transplants & implants Tumors Uncertainty Xenograft Model Antitumor Assays Xenografts Xenotransplantation
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-31830-2