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

Stoletov K, Willetts L, Paproski RJ, Bond DJ, Raha S, Jovel J, Adam B, Robertson AE, Wong F, Woolner E, Sosnowski DL, Bismar TA, Wong GK, Zijlstra A, Lewis JD
Nat Commun. 2018 9 (1): 2343

PMID: 29904055 · PMCID: PMC6002534 · DOI:10.1038/s41467-018-04743-2

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.

MeSH Terms (20)

Animals Cell Line, Tumor Cell Movement Chick Embryo Collagen Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Male Mice Mice, Nude Mice, SCID Neoplasm Invasiveness Neoplasm Metastasis Neoplasm Transplantation Phenotype Prostatic Neoplasms RNA, Small Interfering RNA Interference

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