Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism

RM Perera, S Stoykova, BN Nicolay, KN Ross… - Nature, 2015 - nature.com
RM Perera, S Stoykova, BN Nicolay, KN Ross, J Fitamant, M Boukhali, J Lengrand…
Nature, 2015nature.com
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 …
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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