Abstract
Abstract We previously identified the mechanistic Target of Rapamycin Complex 2 (mTORC2) as an effector of Ras for the control of directed cell migration in Dictyostelium. Recently, this relationship was found to be conserved in mammalian cells, and mTORC2 was shown to be an effector of oncogenic Ras. Deregulated mTORC2 signaling in cancer is mostly associated with increased survival and metabolic reprogramming, but mTORC2 has also been linked to cancer cell migration, particularly in breast cancer. Interestingly, although Ras is rarely mutated in breast cancer, it is often upregulated due to amplification and overexpression of growth factor receptors. Here, we investigated the role of Ras in promoting the migration and invasion of breast cancer cells through mTORC2. We observed that Ras and mTORC2 promote the migration of breast cancer cells, independently of the breast cancer molecular subtype. Using breast epithelial MCF10A cells transformed with HER2 or mutant Ras, we found that Ras promotes mTORC2 activation, and mTORC2-dependent migration and invasion. We further observed that while mutant Ras-transformed MCF10A cells display uncontrolled cell proliferation and an invasive phenotype, silencing of the mTORC2-dependent component Rictor mostly leads to loss of invasiveness. Together, our findings suggest that, whereas Ras activation of mTORC2 is likely to play a minor role in breast tumor formation, the Ras-mTORC2 pathway plays a key and general role in promoting the migration and invasion of breast cancer cells. Citation Format: Mollie E. Wiegand, Shannon E. Collins, Isabella N. Brown, Alyssa N. Werner, Isabelle M. Mundo, Ghassan Mouneimne, Pascale G. Charest. Ras-mediated activation of mTORC2 drives breast cancer cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2416.
Published Version
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