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  • Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.

Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.

Nature (2015-07-15)
Rushika M Perera, Svetlana Stoykova, Brandon N Nicolay, Kenneth N Ross, Julien Fitamant, Myriam Boukhali, Justine Lengrand, Vikram Deshpande, Martin K Selig, Cristina R Ferrone, Jeff Settleman, Gregory Stephanopoulos, Nicholas J Dyson, Roberto Zoncu, Sridhar Ramaswamy, Wilhelm Haas, Nabeel Bardeesy
ABSTRACT

Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we 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 of transcription factors. In human PDA cells, the MiT/TFE proteins--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-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.

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