Jayanta Debnath, MD

Professor
Department of Pathology
+1 415 476-1780

Autophagy In Cell Survival and Cancer Progression

Autophagy is a fundamental catabolic process in which a cell literally “eats itself”. During autophagy, the cytoplasm and organelles of a cell are sequestered within double membrane vacuoles, called autophagosomes, and subsequently delivered to the lysosome for degradation. In eukaryotic cells, autophagy primarily functions as a critical survival response during nutrient deprivation or stress; as a result, interest in manipulating this tightly controlled self-eating process to treat human diseases, such as cancer, has rapidly intensified.

My laboratory focuses how autophagy contributes to cell survival and cancer progression using both in vitro and in vivo models. Our three main goals are: 1) determine the role of autophagy in cancer metabolism, cell survival and oncogenic transformation; 2) delineate the role of autophagy in cancer progression and metastasis in vivo; and 3) dissect the biological and biochemical functions of the molecules that control autophagy (called ATGs) to ultimately exploit this process for therapeutic benefit.

Ongoing Research:

Autophagy, metabolic fitness, and oncogenic transformation: Cancer cells are resistant to anoikis, a form of apoptosis observed in epithelial cells deprived of extracellular matrix (ECM) contact. Several years ago, we discovered that autophagy serves as a mechanism of anoikis resistance. In follow-up work, we have discovered that autophagy also facilitates glycolytic metabolism during oncogenic transformation. Based on these findings, we are dissecting how autophagy contributes to the metabolic fitness of oncogene-transformed cells, allowing them to survive and expand in response to ECM deprivation and other microenvironmental stresses.

Autophagy in cancer progression and metastases: My laboratory is also delineating how autophagy impacts breast cancer progression in vivo using mouse cancer models. We have created mice containing conditional null mutant alleles that allow us to delete autophagy in a tissue specific manner. We are now crossing with established mouse models of metastatic breast cancer to define the role of autophagy in cancer progression in vivo. Our studies focus on dissecting the functional requirements for autophagy in both tumor cells as well as key stromal constituents of the larger tumor microenvironment during primary tumor growth and metastasis.

Novel biochemical and biological functions of ATGs: Despite widespread interest in exploiting autophagy for therapeutic purposes, we have much to learn about how this process works in mammalian cells and tissues. Autophagy is a tightly regulated by highly conserved gene products called ATGs. However, our recent results implicate these ATGs in diverse cellular functions that are distinct from their long-established roles in classical autophagy. Using cell biological, biochemical and yeast genetic approaches, we are: 1) dissecting new roles for ATGs in the control of secretion and adhesion; 2) probing genetic interactions between autophagy and mitochondrial protein quality control pathways; 3) elucidating the cellular functions of ATG12-ATG3, a novel complex between two autophagy regulators discovered in my laboratory, in the control of endocytosis and exosome biogenesis; and 4) determining how autophagy impacts protein translation during starvation.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Research Summary: 
Autophagy In Cell Survival and Cancer Progression

Websites

Featured Publications: 

NBR1 enables autophagy-dependent focal adhesion turnover.

The Journal of cell biology

Kenific CM, Stehbens SJ, Goldsmith J, Leidal AM, Faure N, Ye J, Wittmann T, Debnath J

Autophagy at the crossroads of catabolism and anabolism.

Nature reviews. Molecular cell biology

Kaur J, Debnath J

Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection.

Nature

Kimmey JM, Huynh JP, Weiss LA, Park S, Kambal A, Debnath J, Virgin HW, Stallings CL

Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion.

Cancer discovery

Lock R, Kenific CM, Leidal AM, Salas E, Debnath J

FOXO3A directs a protective autophagy program in haematopoietic stem cells.

Nature

Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J, Passegué E

Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation.

Molecular biology of the cell

Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, Debnath J

Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST).

Proceedings of the National Academy of Sciences of the United States of America

Gupta A, Roy S, Lazar AJ, Wang WL, McAuliffe JC, Reynoso D, McMahon J, Taguchi T, Floris G, Debiec-Rychter M, Schoffski P, Trent JA, Debnath J, Rubin BP

ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death.

Cell

Radoshevich L, Murrow L, Chen N, Fernandez E, Roy S, Fung C, Debnath J