Jayanta Debnath, Tim Marsh, Candia Kenific, Andrew Leidal, Ariadne Vlahakis, Deepthisri Suresh, and Daphne Superville UCSF, San Francisco, USA Autophagy has been proposed as a potential therapeutic target in metastasis, with several studies suggesting that autophagy promotes the metastatic properties of tumor cells. Here, we demonstrate a dual and stage-specific role for autophagy during metastatic progression in vivo. Utilizing a transgenic mammary model driven by the Polyoma Middle T antigen (PyMT), in which the essential autophagy regulators, ATG12 or ATG5 are temporally deleted in mammary tumor cells during distinct stages of carcinoma progression, we uncover that autophagy promotes primary mammary tumor growth and enables the early stages of metastatic seeding in vivo. In contrast, autophagy restricts metastatic colonization by preventing the outgrowth of tumor cells into macrometastases once they have successfully seeded in the metastatic microenvironment.
Upon preventing the accumulation of the autophagy cargo receptor, Neighbor of BRCA1 (NBR1), in autophagy deficient breast cancer cells, the pro-metastatic effects of autophagy inhibition on metastatic colonization are reversed. In addition, NBR1, but not the related cargo receptor, p62/SQSTM1, is sufficient to drive metastatic growth, even in autophagy-competent breast tumor cells. We are conducting proteomic studies to uncover targets of NBR1-mediated selective autophagy that regulate metastatic colonization; results from these studies will be presented at the meeting. These results point to the stage specific effects of autophagy during mammary cancer metastatic progression and identify NBR1 as a potential therapeutic target in preventing disseminated tumor cells from developing into overt, clinical disease.
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