Overview
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; however, when excessive autophagy occurs in a cell, programmed cell death ensues. Interest in manipulating this tightly controlled self-eating process to treat human diseases, such as neurodegeneration, infectious disease and cancer, has rapidly intensified.
My laboratory focuses how autophagy contributes to epithelial cell survival and cancer using both in vitro and in vivo models. Currently, our three main goals are: 1) determine the role of autophagy in epithelial cell survival and oncogenic transformation; 2) delineate the role of autophagy in tumor 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, adhesion independent survival, and oncogenic transformation: Integrin-mediated cell adhesion to ECM is critical for normal epithelial cell survival; in fact, ECM-deprived normal cells (unlike cancer cells) undergo apoptosis, termed anoikis. Constitutive growth factor pathway activation is a common mechanism utilized by cancer cells to evade anoikis. However, we discovered autophagy as another mechanism that protects epithelial cells during anoikis. In recent follow-up studies, we have found that autophagy is robustly induced in detached cells expressing oncogenes and have discovered that autophagy facilitates glycolytic metabolism and proliferation during adhesion independent transformation. Based on these findings, we are dissecting how autophagy contributes to the fitness of oncogene-transformed cells, allowing them to survive and expand in the absence of cell-ECM contact.
Autophagy and cancer metastases: In the upcoming years, my laboratory will delineate how autophagy impacts on cancer progression in mouse cancer models. We have created mice containing conditional null mutant alleles of ATG12, allowing us to delete this gene 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 will focus on dissecting the requirements for autophagy in tumor cell survival as they disseminate into the systemic circulation and metastasize to foreign tissue sites.
Novel biochemical and biological functions of ATGs: Despite widespread interest in exploiting autophagy for therapeutic purposes, we have much to learn about this process in mammalian cells and tissues. Autophagy is tightly regulated by highly conserved gene products called ATGs. We are examining the functions of these ATGs using cell biological and biochemical approaches. Our studies primarily focus on ATG12, an ubiquitin-like protein conjugation (UBL) required for autophagy. A long-held view in the autophagy field has been that ATG12 (in contrast to other UBLs) possesses a single substrate, called ATG5. However, we recently discovered that ATG12 is also conjugated to ATG3, another enzyme required for autophagy. As individual proteins, both ATG12 and ATG3 are essential for early autophagosome formation. In contrast, the ATG12-ATG3 protein complex dramatically alters the mitochondrial network and the response to mitochondrial cell death. Overall, these results unveil a previously unrecognized role for ATG12-ATG3 in mitochondrial homeostasis and function and implicate the ATG12 conjugation system in cellular functions distinct from the early steps of autophagosome formation.
The Role of Autophagy in Tumor Progression:
