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Nature. 2015 Aug 20;524(7565):361-5. doi: 10.1038/nature14587. Epub 2015 Jul 13.

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

Author information

  • 1Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • 2Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • 3Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
  • 4Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • 5Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • 6Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  • 7Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.

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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PMID:
26168401
PMCID:
PMC5086585
DOI:
10.1038/nature14587
[PubMed - indexed for MEDLINE]
Free PMC Article
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