CRISPR-Cas9 Screen identifies NF2 as a target to attenuate oncogenic responses to TGFb1 in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most pernicious types of tumors, with severely limited treatment options. PDAC hallmarks include aggressive local proliferation and invasiveness. This phenotype is supported by upregulated epithelial-to-mesenchymal transition (EMT), typically induced by aberrant transforming growth factor-b (TGFb) signaling. It is, however, unknown whether TGFb-induced EMT and loss of NF2 are causally related, since previous studies correlated the expression of NF2 with poor survival of pancreatic cancer patients, however, the underlying mechanisms remain poorly defined. We performed that in genome-wide CRISPR-Cas9 loss-of-function screens and identify NF2 as a TGF-b target gene. Subsequently, our results indicate that cell proliferation and migration activities were significantly increased in NF2 knockouts compared with parental cells in vitro and in vivo. Here, we demonstrate the absence of NF2 can regulate cell proliferation, migration, and induction of EMT by preventing TGFb1 induction. Collectively, our findings establish a new role for NF2 as a tumor suppressor, raising implications for understanding the contribution(s) of NF2 to TGF-b function in PDAC.