title: Glioblastomas require integrin αvβ3/PAK4 signaling to escape senescence.
abstract: Integrin αvβ3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin αvβ3 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 αvβ3 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, αvβ3/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 αvβ3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.
authors: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors: Aleksandra
authors: A
authors: Franovic
authors: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors: Kathryn C
authors: KC
authors: Elliott
authors: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors: Laetitia
authors: L
authors: Seguin
authors: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors: M Fernanda
authors: MF
authors: Camargo
authors: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors: Sara M
authors: SM
authors: Weis
authors: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California. dcheresh@ucsd.edu.
authors: David A
authors: DA
authors: Cheresh
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D019096:Vitronectin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D039302:Integrin alphaVbeta3; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D019096:Vitronectin; C116367:PAK4 protein, human; D054462:p21-Activated Kinases