Transcriptional Control of Autophagy-Lysosome Function Drives Pancreatic Cancer Metabolism

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acids / metabolism
  • Animals
  • Autophagy / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Energy Metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Heterografts
  • Homeostasis
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Mice
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • Amino Acids
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • TFE3 protein, human
  • TFEB protein, human
  • Transcription Factors

Associated data

  • GEO/GSE62077