Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis

Konstantin Stoletov, Lian Willetts, Robert J. Paproski, David J. Bond, Srijan Raha, Juan Jovel, Benjamin Adam, Amy E. Robertson, Francis Wong, Emma Woolner, Deborah L. Sosnowski, Tarek A. Bismar, Gane Ka-Shu Wong, Andries Zijlstra and John D. Lewis ()
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Konstantin Stoletov: University of Alberta
Lian Willetts: University of Alberta
Robert J. Paproski: University of Alberta
David J. Bond: University of Alberta
Srijan Raha: University of Alberta
Juan Jovel: University of Alberta
Benjamin Adam: University of Alberta
Amy E. Robertson: University of Alberta
Francis Wong: University of Alberta
Emma Woolner: University of Alberta
Deborah L. Sosnowski: University of Alberta
Tarek A. Bismar: University of Calgary Cumming School of Medicine and Calgary Laboratory Services
Gane Ka-Shu Wong: University of Alberta
Andries Zijlstra: Vanderbilt University
John D. Lewis: University of Alberta

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.

Date: 2018
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DOI: 10.1038/s41467-018-04743-2

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