biostudies-literatureFranovic ANCI NIH HHSCanadian Institutes of Health Research4466-73https://www.ebi.ac.uk/biostudies/studies/S-EPMC4631634biostudies-literatureUnknown75(21)Integrin ?v?3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin ?v?3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either ?v?3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, ?v?3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the ?v?3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.Cancer researchGlioblastomas require integrin ?v?3/PAK4 signaling to escape senescence.PMC4631634R01 CA045726R01 CA45726R01 CA168692Elliott KCCheresh DAWeis SMCamargo MFFranovic ASeguin LfalseGlioblastomas require integrin ?v?3/PAK4 signaling to escape senescence.Integrin ?v?3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin ?v?3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either ?v?3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, ?v?3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the ?v?3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.2015-01-01T00:00:00Z2015 Nov2020-11-19T15:30:20Z2019-03-27T02:01:16ZS-EPMC46316342629773510.1158/0008-5472.CAN-15-098810.1158/0008-5472.can-15-0988