In vivo CRISPR screens reveal SCAF1 and USP15 as novel drivers of pancreatic cancer

Functionally characterizing the genetic alterations that drive pancreatic cancer progression is a prerequisite for precision pedicine. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to assess the transforming potential of 125 recurrently mutated ‘long-tail’ pancreatic cancer genes, which revealed USP15 and SCAF1 as novel and potent pancreatic ductal adenocarcinoma PDAC tumor suppressors, with USP15 functioning in a haplo-insufficient manner. Mechanistically, we found that loss of USP15 leads to reduced inflammatory responses associated with TNFa, TGF-b and IL6 signaling and sensitizes pancreatic cancer cells to PARP inhibition and Gemcitabine. Similarly, genetic ablation of SCAF1 reduced inflammatory responses linked to TNFa, TGF-b and mTOR signaling and increased sensitivity to PARP inhibition. Furthermore, we identified that loss of SCAF1 resulted in the formation of a truncated inactive USP15 isoform at the expense of full length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 mutations or copy number losses are observed in 31% of PDAC patients. Together, our results demonstrate the utility of in vivo CRISPR screens to integrate human cancer genomics with mouse modeling for selective discovery of novel cancer driver genes such as USP15 and SCAF1 with potential prognostic and therapeutic implications.