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

Zachary Steinhart, Traver Hart, Megha Chandrashekhar, Zvezdan Pavlovic, Mélanie Robitaille, Xiaowei Wang, Jarrett Adams, James Pan, Sachdev Sidhu, Jason Moffat, View ORCID ProfileStéphane Angers
doi: https://doi.org/10.1101/041996
Zachary Steinhart
1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, 144 College Street, University of Toronto, Toronto, Canada, M5S 3M2
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Traver Hart
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
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Megha Chandrashekhar
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
3Department of Molecular Genetics, University of Toronto, Toronto, Canada, M5S1A8
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Zvezdan Pavlovic
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
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Mélanie Robitaille
1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, 144 College Street, University of Toronto, Toronto, Canada, M5S 3M2
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Xiaowei Wang
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
4The Centre for the Commercialization of Antibodies and Biologics, 100 College St., Toronto, Canada, M5G 1L5
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Jarrett Adams
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
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James Pan
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
4The Centre for the Commercialization of Antibodies and Biologics, 100 College St., Toronto, Canada, M5G 1L5
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Sachdev Sidhu
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
3Department of Molecular Genetics, University of Toronto, Toronto, Canada, M5S1A8
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  • For correspondence: stephane.angers@utoronto.ca j.moffat@utoronto.ca sachdev.sidhu@utoronto.ca
Jason Moffat
2Donnelly Centre, 160 College Street, University of Toronto, Toronto, Canada, M5S3E1
3Department of Molecular Genetics, University of Toronto, Toronto, Canada, M5S1A8
6Canadian Institute for Advanced Research, Toronto, Canada, M5G1Z8
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  • For correspondence: stephane.angers@utoronto.ca j.moffat@utoronto.ca sachdev.sidhu@utoronto.ca
Stéphane Angers
1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, 144 College Street, University of Toronto, Toronto, Canada, M5S 3M2
5Department of Biochemistry, University of Toronto, Toronto, Canada.
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  • ORCID record for Stéphane Angers
  • For correspondence: stephane.angers@utoronto.ca j.moffat@utoronto.ca sachdev.sidhu@utoronto.ca
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Abstract:

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.

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Posted March 01, 2016.
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A CRISPR screen reveals a WNT7B-FZD5 signaling circuit as a therapeutic opportunity in pancreatic cancer
Zachary Steinhart, Traver Hart, Megha Chandrashekhar, Zvezdan Pavlovic, Mélanie Robitaille, Xiaowei Wang, Jarrett Adams, James Pan, Sachdev Sidhu, Jason Moffat, Stéphane Angers
bioRxiv 041996; doi: https://doi.org/10.1101/041996
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A CRISPR screen reveals a WNT7B-FZD5 signaling circuit as a therapeutic opportunity in pancreatic cancer
Zachary Steinhart, Traver Hart, Megha Chandrashekhar, Zvezdan Pavlovic, Mélanie Robitaille, Xiaowei Wang, Jarrett Adams, James Pan, Sachdev Sidhu, Jason Moffat, Stéphane Angers
bioRxiv 041996; doi: https://doi.org/10.1101/041996

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