Autophagy is a tightly regulated intracellular degradation and recycling process that is crucial for cellular homeostasis and adaptation to diverse cancer-relevant stresses. In cancer, current research suggests that autophagy promotes the survival and metabolic fitness of tumors during stress and serves as a resistance pathway during chemotherapy. This has generated significant interest in autophagy inhibition as a therapeutic strategy in cancer; indeed, anti-malarials such as hydroxychloroquine (HCQ) are currently being repurposed as autophagy inhibitors in numerous clinical oncology trials, largely due to their long history of use in humans and well-established toxicity profiles. Despite this enthusiasm, we have much to learn about the long-term consequences of autophagy inhibition in cancer therapy. An important unanswered question is how autophagy impacts metastasis, a principal cause of cancer mortality. The functions of autophagy during metastasis have not been rigorously tested in vivo and our preliminary studies in mouse mammary cancer models indicate that autophagy inhibition in tumor cells results in increased, not decreased, metastasis. These unexpected findings raise the possibility that pharmacological autophagy inhibitors like HCQ may harbor long-term risks by enhancing metastasis in certain cancer patients. In addition, we have obtained preliminary evidence that two mediators of selective autophagy, p62/SQSTM1 and NBR1, direct how the autophagy pathway influences metastasis and tumor cell proliferation during mammary cancer progression and response to therapy. Based on this preliminary data, this proposal seeks to precisely define the stage at which autophagy suppresses mammary cancer metastasis in vivo and to dissect the mechanisms by which autophagy deficiency promotes the metastatic phenotype. We will employ established immmunocompetent mammary cancer models to scrutinize the functions of the autophagy pathway during metastatic progression in vivo.
In Aim 1, we will determine the stage-specific effects of autophagy in suppressing metastatic seeding and colonization.
In Aim 2, we will determine how p62/SQSTM1 accumulation in autophagy deficient cells impacts metastatic outgrowth.
In Aim 3, we will determine the role of NBR1 in adhesion-mediated signaling and metastasis. Overall, these studies provide unique conceptual insight into the role of autophagy during metastasis.

Public Health Relevance

Despite immense interest in inhibiting autophagy, a tightly regulated lysosomal degradation process, to treat cancer, we have little appreciation for how these strategies will impact metastasis, a principal cause of cancer mortality. By defining the functions of the autophagy pathway during metastasis, this project will provide unique, timely insight into how to most effectively exploit autophagy to treat cancer patients, an issue of immense therapeutic significance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Woodhouse, Elizabeth
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Monkkonen, Teresa; Debnath, Jayanta (2018) Inflammatory signaling cascades and autophagy in cancer. Autophagy 14:190-198
Cadwell, Ken; Debnath, Jayanta (2018) Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins. J Cell Biol 217:813-822
Roy, Srirupa; Leidal, Andrew M; Ye, Jordan et al. (2017) Autophagy-Dependent Shuttling of TBC1D5 Controls Plasma Membrane Translocation of GLUT1 and Glucose Uptake. Mol Cell 67:84-95.e5
Roy, Srirupa; Debnath, Jayanta (2017) Autophagy enables retromer-dependent plasma membrane translocation of SLC2A1/GLUT1 to enhance glucose uptake. Autophagy 13:2013-2014
Vlahakis, Ariadne; Debnath, Jayanta (2017) The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion. J Mol Biol 429:515-530
Rose, John C; Huang, Po-Ssu; Camp, Nathan D et al. (2017) A computationally engineered RAS rheostat reveals RAS-ERK signaling dynamics. Nat Chem Biol 13:119-126
Kenific, Candia M; Debnath, Jayanta (2016) NBR1-dependent selective autophagy is required for efficient cell-matrix adhesion site disassembly. Autophagy 12:1958-1959
Liu, J; Debnath, J (2016) The Evolving, Multifaceted Roles of Autophagy in Cancer. Adv Cancer Res 130:1-53
Altshuler-Keylin, Svetlana; Shinoda, Kosaku; Hasegawa, Yutaka et al. (2016) Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. Cell Metab 24:402-419
Kenific, Candia M; Stehbens, Samantha J; Goldsmith, Juliet et al. (2016) NBR1 enables autophagy-dependent focal adhesion turnover. J Cell Biol 212:577-90

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