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Abstract

Autophagy is a conserved catabolic process critical for the degradation of damaged organelles and protein aggregates as well as the intracellular recycling of proteins and lipids. Autophagy occurs at a basal rate in all cells and may be upregulated under conditions of stress; in particular, some tumor cells utilize autophagy to survive nutrient stress, hypoxic conditions, and cytotoxic therapies. Research into the role of autophagy in primary tumor growth suggests that autophagy may be tumor suppressive through its promotion of genome stability, limitation of necrosis and inflammation, and induction of growth arrest. However, other studies indicate a tumor-promoting role for autophagy, highlighting the fact that the role of autophagy is highly context-dependent, varying with oncogenic status, state of progression, and environment. With respect to metastasis, autophagy can facilitate the survival of tumor cells during detachment from the extracellular matrix, withdrawal of growth factors, and glucose deprivation. Additionally, autophagy is upregulated under conditions that promote metastasis, including hypoxia and TGFβ exposure. Finally, clinical studies have correlated increased autophagic flux with tumor metastases. Previous work in our lab has demonstrated that autophagy is not required for primary tumor growth in the 4T1 orthotopic murine model of breast cancer but is critical to the formation of metastases. In vitro, autophagy-deficient tumor cells exhibit a rounded morphology and impaired motility; this phenotype is due to the impaired disassembly of focal adhesions. Therefore, I sought to determine the mechanism by which autophagy inhibition prevents focal adhesion disassembly and inhibits metastasis. I demonstrate that the levels of the focal adhesion protein paxillin are dependent on autophagy but that the p62/Sqstm1 and Nbr1 cargo adaptors are dispensable for paxillin. Furthermore, I demonstrate that paxillin can bind LC3B directly and that the conserved LC3-interacting region motif in paxillin is required for binding and subsequent cell motility. Finally, oncogenic Src can stimulate the binding of paxillin with LC3B, and the ability of Src to promote cell motility requires intact autophagy. These results establish a novel function for autophagy in tumor motility and metastasis by promoting paxillin degradation.

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