The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
CRISPR/Cas9-Mediated Trp53 and Brca2 Knockout to Generate Improved Murine Models of Ovarian High-Grade Serous Carcinoma
Open accessAbstract
There is a need for transplantable murine models of ovarian high-grade serous carcinoma (HGSC) with regard to mutations in the human disease to assist investigations of the relationships between tumor genotype, chemotherapy response, and immune microenvironment. In addressing this need, we performed whole-exome sequencing of ID8, the most widely used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400× with 90% exons sequenced >50×. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, and Rb1), and p53 remained transcriptionally active. Homologous recombination in ID8 remained intact in functional assays. Further, we found no mutations typical of clear cell carcinoma (Arid1a, Pik3ca), low-grade serous carcinoma (Braf), endometrioid (Ctnnb1), or mucinous (Kras) carcinomas. Using CRISPR/Cas9 gene editing, we modeled HGSC by generating novel ID8 derivatives that harbored single (Trp53–/–) or double (Trp53–/–;Brca2–/–) suppressor gene deletions. In these mutants, loss of p53 alone was sufficient to increase the growth rate of orthotopic tumors with significant effects observed on the immune microenvironment. Specifically, p53 loss increased expression of the myeloid attractant CCL2 and promoted the infiltration of immunosuppressive myeloid cell populations into primary tumors and their ascites. In Trp53–/–;Brca2–/– mutant cells, we documented a relative increase in sensitivity to the PARP inhibitor rucaparib and slower orthotopic tumor growth compared with Trp53–/– cells, with an appearance of intratumoral tertiary lymphoid structures rich in CD3+ T cells. This work validates new CRISPR-generated models of HGSC to investigate its biology and promote mechanism-based therapeutics discovery. Cancer Res; 76(20); 6118–29. ©2016 AACR.
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Cites
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133
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Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer
Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., Makrigiannakis, A., Gray, H., Schlienger, K., Liebman, M. N., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa020177 · Cited by 3,397
GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases
Tsai, S. Q., Zheng, Z., Nguyen, N. T., Liebers, M., Topkar, V. V., Thapar, V., Wyvekens, N., Khayter, C., Iafrate, A. J., Le, L. P., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3117 · Cited by 2,268
Digenome-seq: Genome-wide profiling of CRISPR-cas9 off-target effects in human cells
Kim, D., Bae, S., Park, J., Kim, E., Kim, S., Yu, H. R., Hwang, J., Kim, J.-I., & Kim, J.-S. (2015) · Nature Methods · doi:10.1038/nmeth.3284 · Cited by 992
Perets, R., Wyant, G. A., Muto, K. W., Bijron, J. G., Poole, B. B., Chin, K. T., Chen, J. Y. H., Ohman, A. W., Stepule, C. D., Kwak, S., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.10.013 · Cited by 596
Development of a Syngeneic Mouse Model for Events Related to Ovarian Cancer
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p53 is an important regulator of CCL2 gene expression
Tang, X., Asano, M., O’Reilly, A., Farquhar, A., Yang, Y., & Amar, S. (2012) · Current Molecular Medicine · doi:10.2174/156652412802480844 · Cited by 30
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p53, cancer and the immune response
Blagih, J., Buck, M. D., & Vousden, K. H. (2020) · Journal of Cell Science · doi:10.1242/jcs.237453 · Cited by 333
Self-citationActivating a collaborative innate-adaptive immune response to control metastasis
Sun, L., Kees, T., Almeida, A. S., Liu, B., He, X.-Y., Ng, D., Han, X., Spector, D. L., McNeish, I. A., Gimotty, P., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.08.005 · Cited by 267
Self-citationChehelgerdi, M., Chehelgerdi, M., Khorramian-Ghahfarokhi, M., Shafieizadeh, M., Mahmoudi, E., Eskandari, F., Rashidi, M., Arshi, A., & Mokhtari-Farsani, A. (2024) · Molecular Cancer · doi:10.1186/s12943-023-01925-5 · Cited by 251
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Diaz Osterman, C. J., Ozmadenci, D., Kleinschmidt, E. G., Taylor, K. N., Barrie, A. M., Jiang, S., Bean, L. M., Sulzmaier, F. J., Jean, C., Tancioni, I., et al. (2019) · eLife · doi:10.7554/elife.47327 · Cited by 145
Metadata
- Authors
- Walton, J., Blagih, J., Ennis, D., Leung, E., Dowson, S., Farquharson, M., Tookman, L. A., Orange, C., Athineos, D., Mason, S., Stevenson, D., Blyth, K., Strathdee, D., Balkwill, F. R., Vousden, K., Lockley, M., & McNeish, I. A.
- Venue
- Cancer Research
- Published
- 2016-10-13
- Volume
- 76
- Issue
- 20
- Pages
- 6118-6129
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2513362995
- Cited by
- 237
- References
- 8
- FWCI
- 14.61
- Type
- journal article
- Language
- en
- Open access
- green
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- Walton, J., Blagih, J., Ennis, D., Leung, E., Dowson, S., Farquharson, M., Tookman, L. A., Orange, C., Athineos, D., Mason, S., Stevenson, D., Blyth, K., Strathdee, D., Balkwill, F. R., Vousden, K., Lockley, M., & McNeish, I. A. (2016). CRISPR/Cas9-Mediated Trp53 and Brca2 Knockout to Generate Improved Murine Models of Ovarian High-Grade Serous Carcinoma. Cancer Research. https://doi.org/10.1158/0008-5472.can-16-1272
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