PT  - JOURNAL ARTICLE
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
TI  - A CRISPR screen reveals a WNT7B-FZD5 signaling circuit as a therapeutic opportunity in pancreatic cancer
AID  - 10.1101/041996
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 041996
4099  - http://biorxiv.org/content/early/2016/03/01/041996.short
4100  - http://biorxiv.org/content/early/2016/03/01/041996.full
AB  - 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.