Existing anti-cancer strategies focused on disrupting integrin functions
in tumor cells or tumor-involved endothelial cells have met limited success. An
alternative strategy is to augment integrin-mediated pathways that suppress
tumor progression, but how integrins can signal to restrain malignant behavior
remains unclear. To address this issue, we generated an in vivo model of
prostate cancer metastasis via depletion of α3β1 integrin, a
correlation observed in a significant proportion of prostate cancers. Our data
describe a mechanism whereby α3β1 signals through Abl family
kinases to restrain Rho GTPase activity, support Hippo pathway suppressor
functions, and restrain prostate cancer migration, invasion, and
anchorage-independent growth. This α3β1-Abl kinase-Hippo
suppressor pathway identified α3 integrin-deficient prostate cancers as
potential candidates for Hippo-targeted therapies currently under development,
suggesting new strategies for targeting metastatic prostate cancer based on
integrin expression. Our data also revealed paradoxical tumor suppressor
functions for Abl kinases in prostate cancer that may help to explain the
failure of Abl kinase inhibitor imatinib in prostate cancer clinical trials.
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