Rxivist logo

A CRISPR screen reveals a WNT7B-FZD5 signaling circuit as a therapeutic opportunity in pancreatic cancer.

By Zachary Steinhart, Traver Hart, Megha Chandrashekhar, Zvezdan Pavlovic, Mélanie Robitaille, Xiaowei Wang, Jarrett Adams, James Pan, Sachdev Sidhu, Jason Moffat, Stephane Angers

Posted 01 Mar 2016
bioRxiv DOI: 10.1101/041996

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.

Download data

  • Downloaded 2,685 times
  • Download rankings, all-time:
    • Site-wide: 3,887 out of 118,130
    • In cancer biology: 62 out of 3,742
  • Year to date:
    • Site-wide: 39,956 out of 118,130
  • Since beginning of last month:
    • Site-wide: 45,367 out of 118,130

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News