AUTOPHAGY REGULATION IN PANCREATIC CANCER
Autophagy (also known as macroautophagy), is a cellular self-catabolic process, conserved from yeast to man, that mediates degradation of macromolecules and even whole organelles. Decreases in extracellular or intracellular nutrient levels serve as potent activators of autophagy while nutrient abundance suppresses this pathway. The process of autophagy involves generation of a double membrane vesicle (the autophagosome), which encapsulates cytoplasmic contents followed by delivery to lysosomes for cargo degradation. Substrates for autophagy-mediated degradation are diverse and include misfolded proteins, damaged organelles, protein aggregates and lipid droplets. Digestion of these products in lysosomes yields essential building blocks, which can be recycled back to the cytoplasm to fuel biosynthetic and bioenergetic reactions and ultimately protect the cell during conditions of nutrient starvation while also providing an important quality control mechanism. Deregulation of autophagy has been implicated in the pathogenesis of degenerative and immune disorders as well as in aging. Numerous studies have also highlighted an essential role for autophagy in cancer.
We have identified the MiT/TFE family of transcription factors (TFE3, MITF, and TFEB) as master regulators of autophagy-lysosome activation in PDA. Through enhanced binding to nuclear import proteins, these factors are constitutively localized in the nucleus where they orchestrate transcriptional control of the biogenesis and function of the autophagosome-lysosome system.
Building on these findings, we are interested in understanding in greater detail the regulatory circuits controlling sustained autophagy induction both at the transcriptional and signaling levels in PDA cells.
ORGANELLE FUNCTION AND METABOLISM
The final step of autophagy involves fusion with lysosomes and breakdown of cargo by resident lysosomal enzymes. These products of lysosomal digestion can be recycled back to the cell and incorporated into synthesis of new macromolecules or used to maintain cellular bioenergetics. We have shown that the increased catabolic activity intrinsic to PDA cells is important for maintenance of intracellular amino acid levels. Furthermore the MiT/TFE factors are at the nexus of autophagy activation and lysosome function and are required to sustain the metabolic state of PDA cells. We are interested in understanding how lysosome-derived metabolites are utilized and how they contribute to the ability of PDA cells to thrive under varying nutrient conditions in vivo. Using a combination of metabolite tracing and proteomics analysis we will begin to unravel the pathways specifically fueled by lysosome derived amino acids. These pathways may in turn represent novel targets for development of anti-cancer therapies.
We are grateful for funding from the following agencies: