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Novel functions for autophagy during Ras transformation
- Lock, Rebecca
- Advisor(s): Evan, Gerard
Abstract
Autophagy is a highly regulated catabolic process that degrades cytosolic organelles and macromolecules. Deregulation of the autophagic process has been linked to the development of several pathologies, including cancer, where it is associated with both pro- and anti-tumor functions. Although multiple studies have provided mechanistic insight into how autophagy suppresses tumorigenesis, the mechanisms explaining a pro-tumor role for autophagy have been limited to its capacity to promote tumor cell viability in response to stress. We hypothesized that autophagy contributes to additional cellular processes that support oncogenic transformation, and here we identify previously unrecognized pro-tumor functions for autophagy in the context of oncogenic Ras.
Using autophagy deficient cells, generated through genetic deletion or RNAi-mediated depletion of critical autophagy genes, we have identified a unique function for autophagy in supporting Ras-mediated anchorage-independent growth and proliferation. Furthermore, in the context of constitutively active Ras autophagy facilitates an enhanced rate of glycolysis, which supports robust anchorage-independent growth. Using a three-dimensional epithelial culture model, we demonstrate a requirement for autophagy in facilitating tumor cell invasion and motility in Ras transformed cells. This reduction in invasive capacity correlates with a partial restoration in cell-cell junctional integrity and polarized secretion of basement membrane proteins. In addition, autophagy supports Ras-driven mesenchymal differentiation and the production of multiple secreted factors required for cell migration and invasion. Overall, these data reveal multiple tumor-promoting functions for autophagy during Ras transformation. Based on our findings we propose that in addition to its widely established function in promoting tumor cell survival, autophagy facilitates a larger repertoire of pro-tumor activities that support cancer progression and metastasis.
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