Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism
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Transcriptional control.pdf
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Author(s)
Perera, Rushika M.
Stoykova, Svetlana
Nicolay, Brandon N.
Ross, Kenneth N.
Fitamant, Julien
Boukhali, Myriam
Lengrand, Justine
Deshpande, Vikram
Selig, Martin K.
Ferrone, Cristina R.
Date Issued
July 2015
Journal
Nature
Publisher
Nature Publishing Group
Citation
Perera, Rushika M.; Stoykova, Svetlana; Nicolay, Brandon N.; Ross, Kenneth N.; Fitamant, Julien; Boukhali, Myriam; Lengrand, Justine et al. “Transcriptional Control of Autophagy–lysosome Function Drives Pancreatic Cancer Metabolism.” Nature 524, no. 7565 (July 2015): 361–365 © 2015 Macmillan Publishers Limited, part of Springer Nature
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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DOI of Published Version
https://doi.org/10.1038/nature14587
