Autophagy Heterogeneity and Tumor Metastasis

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The goal of this project is to investigate the intratumoral heterogeneity of autophagy activity in breast cancer metastasis. Autophagy is a highly conserved lysosomal degradation pathway that is induced in response to environmental or intracellular stress for the recycling of damaged proteins or organelles and the maintenance of cellular homeostasis. While autophagy serves as a tumor suppressor to limit malignant transformation, it also enables the growth and survival of cancer cells within the nutrient- and oxygen-deprived tumor microenvironment (TME). Hypoxia is associated with enhanced metastasis and poor prognosis; however, the role of hypoxia- induced autophagy in tumor progression is not clear. We have established a novel orthotopic model of breast cancer in which autophagy is physiologically and reversibly suppressed in hypoxic tumor regions. Notably, the loss of autophagy in hypoxic tumor regions significantly increases lung metastasis without affecting primary tumor growth. Moreover, the loss of hypoxia-induced autophagy also enhances lung metastasis compared to tumors in which autophagy is constitutively suppressed. Collectively, we hypothesize that the loss of hypoxia- induced autophagy increases tumor stress to promote metastasis via collaboration with nearby autophagy- competent cells to establish tumor subpopulations with high and low autophagic activity that drive metastasis through the fibronectin-integrin signaling and metabolic coupling. The hypotheses will be tested in two Specific Aims: 1) To identify and characterize the tumor subpopulations with increased metastatic potential during the loss of hypoxia-induced autophagy or induction of autophagy heterogeneity; 2) To investigate the mechanisms by which heterogeneous autophagy activity mediates intra-tumor cell communication. Completion of these studies will significantly enhance our understanding of autophagy in tumor metastasis and provide insight into the appropriate modulation of autophagy for cancer therapy.