TY - JOUR T1 - A CRISPR screen reveals a WNT7B-FZD5 signaling circuit as a therapeutic opportunity in pancreatic cancer JF - bioRxiv DO - 10.1101/041996 SP - 041996 AU - Zachary Steinhart AU - Traver Hart AU - Megha Chandrashekhar AU - Zvezdan Pavlovic AU - Mélanie Robitaille AU - Xiaowei Wang AU - Jarrett Adams AU - James Pan AU - Sachdev Sidhu AU - Jason Moffat AU - Stéphane Angers Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/03/01/041996.abstract N2 - CRISPR-Cas9 genome editing enables high-resolution detection of genetic vulnerabilities of cancer cells. We conducted a genome-wide CRISPR-Cas9 screen in RNF43 mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation, and discovered a unique requirement for a WNT7B-FZD5 signaling circuit. Our results highlight an underappreciated level of functional specificity at the ligand-receptor level. We derived a panel of recombinant antibodies that reports the expression of nine out of ten human Frizzled receptors and confirm that WNT7B-FZD5 functional specificity cannot be explained by protein expression patterns. We developed two human antibodies that target FZD5 and robustly inhibited the growth of RNF43 mutant PDAC cells grown in vitro and as xenografts, providing strong orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring a RNF43 variant previously associated with PDAC was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. ER -