US EPA

7105168 

Journal Article 

Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism 

Perera, R; Ferrone, CR; Settleman, J; Stephanopoulos, G; Dyson, NJ; Zoncu, R; Ramaswamy, S; Haas, W; Bardeesy, N; Stoykova, S; Nicolay, BN; Ross, KN; Fitamant, J; Boukhali, M; Lengrand, J; Deshpande, V; Selig, MK; , 

2015 

1 

Nature
ISSN: 0028-0836
EISSN: 1476-4687 

NATURE PUBLISHING GROUP 

LONDON 

524 

7565 

361-U251 

English 

26168401 

10.1038/nature14587 

WOS:000359714000038 

Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers(1). The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy(2-4), a conserved self-degradative process(5). 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(6)-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.