Development of novel in vivo genome engineering approaches for cancer research
Cancer develops from mutations and copy number alterations in oncogenes and tumor suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Our lab is pioneering the use of GEMMs of lung cancer in combination with in vivo CRISPR/Cas9 genome engineering approaches to address the immediate need to systematically interrogate the complex catalog of mutations obtained from cancer genome sequencing studies.
In the era of personalized medicine, CRISPR/Cas9-based approaches provide invaluable tools to tackle the complexity of cancers. The extensive information recorded from an individual patient tumor can be functionally validated using a platform that makes use of both in vitro and in vivo CRIPSR/Cas9-based approaches. Once important functional variants are identified, genetic and drug screens can be performed to identify genotype-specific vulnerabilities that may pave the road to new personalized genotype-based therapies, which is the ultimate goal of precision medicine.
Sayin VI,Papagiannakopoulos T. Application of CRISPR-mediated genome engineering in cancer research.Cancer Lett. 2016 Mar 18. pii: S0304-3835(16)30179-3. doi: 10.1016/j.canlet.2016.03.029. [Epub ahead of print] PMID: 27000990
Sánchez-Rivera, F. J. *;Papagiannakopoulos, T.*; Romero, R.; Tammela, T.; Bauer, M. R.; Bhutkar, A.; Joshi, N.S.; Subbaraj, L.; Bronson, R. T.; Xue, X.; Jacks, T. Rapid modeling of cooperating genetic events in cancer through somatic genome editing. Nature. (2014), doi:10.1038/nature13906 *First Co-Author
Xue, W., Chen, S., Yin, H., Tammela, T.,Papagiannakopoulos, T., Joshi, N. S., Cai, W., Yang, G., Bronson, R., Crowley, D. G., Zhang, F., Anderson, D. G., Sharp, P. A. & Jacks, T. CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature, doi:10.1038/nature13589 (2014).
McFadden DG*,Papagiannakopoulos T.*, Taylor-Weiner A*, Stewart C*, Carter SL*, Cibulskis K, Bhutkar A , McKenna A, Dooley A, Vernon A, Sougnez C, Malstrom S, Heimann M, Park J, Chen F, Farago AF, Dayton T, Shefler E, Gabriel S, Getz G, Jacks T. (2013) Genetic and clonal dissection of murine small cell lung cancer progression by genome sequencing. Cell 156, 1298-1311, doi:10.1016/j.cell.2014.02.031 (2014). *First Co-Authors
