Abstract 2937: The LKB1-STRADα axis regulates vimentin to control cancer cell metastasis

Abstract

Abstract Lung cancer remains the most lethal form of cancer, and non-small cell lung cancer (NSCLC) patients have a 5-year survival rate of only 15-25%. Metastasis is the major cause of death in nearly all cancer cases. Therefore, determining which genes are altered during cancer invasion and the functional consequences of their alteration will broaden our understanding of metastatic disease and unveil novel targets for anti-metastatic therapies. The pleiotropic tumor suppressor LKB1 is mutated in ∼30% of NSCLC cases and is the third most frequently mutated gene in lung adenocarcinoma. Originally recognized as a regulator of the energy stress pathway and cell cycle signaling, we and others have identified LKB1 and its activating co-factor STRADα as regulators of the lung cancer cell polarity program through the small Rho GTPase cdc42 and its downstream binding partner p21-activated kinase (PAK). We expand these studies and investigate the LKB1-STRADα pathway during the transition from cell polarity to cell motility. We show that when a cancer cell becomes motile, STRADα re-localizes to associate with vimentin intermediate filaments in a motility-dependent manner. Vimentin is specifically overexpressed in invasive human tumors, which also correlates with metastatic disease, poor prognosis, and reduced patient survival. To dissect the mechanistic basis of this observation, we tested the hypothesis that STRADα regulates vimentin function to oversee cancer cell motility. STRADα loss results in aberrant lamellipodia formation, uncoordinated movement, and vimentin bundling. Conversely, STRADα overexpression disassembles the vimentin network with no apparent effect on cell survival. A phospho-proteomic screen in isogenic NSCLC cell lines showed that out of 580 possible proteins the cdc42 GEF, VAV2, demonstrated the greatest loss in phosphorylation upon vimentin depletion. Western blot analysis confirmed that vimentin-depletion decreased phosphorylation of VAV2 at residue Y-142. Dual overexpression of LKB1 and STRADα enhances VAV2 phosphorylation in vimentin-positive cells but not in vimentin-depleted cells. These findings suggest a cell polarity-motility program whereby LKB1-STRADα initiates cell polarity through cdc42-PAK, then STRADα re-localizes to the vimentin cytoskeleton to oversee vimentin dynamics. LKB1-STRADα also regulates VAV2 phosphorylation through vimentin signaling. These results link the LKB1-STRADα tumor suppressor pathway to the lung cancer cell polarity and motility programs, and explain how defects in the LKB1-STRADα alter lung cancer invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2937. doi:10.1158/1538-7445.AM2011-2937