Journal Article

Transcriptional control of the autophagy-lysosome system in pancreatic cancer

Deshpande, Vikram, Boukhali, Myriam, Ross, Kenneth N., Perera, Rushika M., Selig, Martin K., Dyson, Nicholas J., Fitamant, Julien, Lengrand, Justine, Settleman, Jeff, Stoykova, Svetlana, Stephanopoulos, Gregory, Zoncu, Roberto, Ramaswamy, Sridhar, Ferrone, Cristina R., Nicolay, Brandon N., Bardeesy, Nabeel, Haas, Wilhelm

2015

Overview

Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers1. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy2–4, a conserved self-degradative process5. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. We now show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family transcription factors. In PDA cells, the MiT/TFE proteins6 – MITF, TFE3 and TFEB – are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosomal activation is specifically required to maintain intracellular amino acid (AA) pools. These results identify the MiT/TFE transcription factors as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate activation of clearance pathways converging on the lysosome as a novel hallmark of aggressive malignancy.