Abstract
Abstract The formation of invasive, rapidly growing metastatic lesions is a critical step in cancer metastasis, the cause of more than 90% of cancer deaths. Development of novel therapeutic approaches that block the invasion step of metastasis is one of the highest priorities for clinical cancer research. For this reason we completed the first genome-wide in vivo shRNA screen for genes that directly contribute to invasive metastatic lesion formation. Using state of the art intravital imaging, we identified over fifty novel regulators of invasive metastatic colony formation in vivo. Interactome analysis links these genes to key cellular processes including: transcriptional regulation of gene expression, mRNA processing and cytoskeletal remodeling. The target list was then prioritized based on clinical gene expression profiles that negatively correlated with key cancer endpoints including metastasis, cancer-specific and overall survival. Pharmacological and shRNA-mediated knockdown of the high priority targets in human cancer cell lines such as prostate cancer and melanoma specifically blocked cancer cell migration and invasion in vitro and in vivo. Moreover, shRNA-mediated knockdown of these genes blocked human cancer cell metastasis in the avian embryo and mouse preclinical models of metastasis. Finally, immunohistochemical analysis on clinical prostate cancer and melanoma tissue samples showed strong correlation with disease progression and metastasis. In summary, we have identified numerous novel genes that that are functionally involved in cancer invasion and metastasis that may serve as predictive markers for disease aggressiveness and represent exciting new pharmacological targets to block cancer invasion and metastasis. Citation Format: Konstantin Stoletov, David Bond, Hon Sing Leong, Emma Woolner, Srijan Raha, Amy Robertson, Francis Wong, Andries Zijlstra, John D. Lewis. In vivo whole genome shRNA screen reveals novel targets to block cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4972. doi:10.1158/1538-7445.AM2014-4972
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