AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma
Author(s)Chow, Ryan D; Guzman, Christopher D; Wang, Guangchuan; Schmidt, Florian; Youngblood, Mark W; Ye, Lupeng; Errami, Youssef; Dong, Matthew B; Martinez, Michael A; Zhang, Sensen; Renauer, Paul; Bilguvar, Kaya; Gunel, Murat; Sharp, Phillip A; Zhang, Feng; Platt, Randall J; Chen, Sidi; ... Show more Show less
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A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m-Nf1, Mll3-Nf1 and Zc3h13-Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Nature Publishing Group
Chow, Ryan D et al. “AAV-Mediated Direct in Vivo CRISPR Screen Identifies Functional Suppressors in Glioblastoma.” Nature Neuroscience 20, 10 (August 2017): 1329–1341 © 2017 Nature America, Inc., part of Springer Nature
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