CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity

Walton, J. B. et al. (2017) CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity. Scientific Reports, 7, 16827. (doi:10.1038/s41598-017-17119-1) (PMID:29203787) (PMCID:PMC5715106)

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Abstract

Transplantable murine models of ovarian high grade serous carcinoma (HGSC) remain an important research tool. We previously showed that ID8, a widely-used syngeneic model of ovarian cancer, lacked any of the frequent mutations in HGSC, and used CRISPR/Cas9 gene editing to generate derivatives with deletions in Trp53 and Brca2. Here we have used one ID8 Trp53−/− clone to generate further mutants, with additional mutations in Brca1, Pten and Nf1, all of which are frequently mutated or deleted in HGSC. We have also generated clones with triple deletions in Trp53, Brca2 and Pten. We show that ID8 Trp53−/−;Brca1−/− and Trp53−/−;Brca2−/− cells have defective homologous recombination and increased sensitivity to both platinum and PARP inhibitor chemotherapy compared to Trp53−/−. By contrast, loss of Pten or Nf1 increases growth rate in vivo, and reduces survival following cisplatin chemotherapy in vivo. Finally, we have also targeted Trp53 in cells isolated from a previous transgenic murine fallopian tube carcinoma model, and confirmed that loss of p53 expression in this second model accelerates intraperitoneal growth. Together, these CRISPR-generated models represent a new and simple tool to investigate the biology of HGSC, and the ID8 cell lines are freely available to researchers.

Item Type:Articles
Additional Information:A correction to this article is available at https://doi.org/10.1038/s41598-018-24099-3.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Coffelt, Dr Seth and Blyth, Dr Karen and Murphy, Dr Daniel and Dowson, Miss Suzanne and Farquharson, Dr Malcolm and Walton, Miss Josephine and Mcneish, Professor Iain and Stevenson, Dr David and PORT, Jennifer and Kruspig, Dr Bjorn and Mason, Ms Susan
Authors: Walton, J. B., Farquharson, M., Mason, S., Port, J., Kruspig, B., Dowson, S., Stevenson, D., Murphy, D., Matzuk, M., Kim, J., Coffelt, S., Blyth, K., and Mcneish, I. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Scientific Reports 7:16827
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
643981Personalised biomarkers of response in high-grade serious ovarian cancerIain McNeishCancer Research UK (CRUK)C608/A15973RI CANCER SCIENCES