Cited by 801Autophagy in Disease and TherapyCalcium signaling and nucleotide metabolismCancer, Hypoxia, and Metabolism

Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism

Open access
Perera, Rushika M., Stoykova, Svetlana, Nicolay, Brandon N., Ross, Kenneth N., Fitamant, Julien, Boukhali, Myriam, Lengrand, Justine, Deshpande, Vikram +9 more·2015·Nature

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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  • DON or its analogs in murine PDAC models appear to have immunomodulatory effects.

    “recent studies have shown that the use of DON or analogs in murine PDAC models also appear to have immunomodulatory effects204,205”

    From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [205]

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Research works printed but not linked: 4

  1. [34]Commisso C Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells Nature 497 633 637 10.1038/nature12138 2013 23665962 PMC3810415 · DOI · Paper page
  2. [38]Settembre C TFEB links autophagy to lysosomal biogenesis Science 332 1429 1433 10.1126/science.1204592 2011 21617040 PMC3638014 · DOI · Paper page
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Authors
Perera, R. M., Stoykova, S., Nicolay, B. N., Ross, K. N., Fitamant, J., Boukhali, M., Lengrand, J., Deshpande, V., Selig, M. K., Ferrone, C. R., Settleman, J., Stephanopoulos, G., Dyson, N. J., Zoncu, R., Ramaswamy, S., Haas, W., & Bardeesy, N.
Affiliations
  • Harvard University (US)
  • Massachusetts General Hospital (US)
  • Massachusetts Institute of Technology (US)
  • University of California, Berkeley (US)
Corresponding author
Bardeesy, Nabeel
Venue
Nature
Published
2015-07-13
Volume
524
Issue
7565
Pages
361-365
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W1678795445
Cited by
799
References
49
Citations by year
2026: 42 · 2025: 59 · 2024: 64 · 2023: 62 · 2022: 84 · 2021: 107 · 2020: 85 · 2019: 76 · 2018: 77 · 2017: 65 · 2016: 63 · 2015: 13 · 2014: 1
FWCI
57.07
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • PMC
Funders
  • Hirshberg Foundation for Pancreatic Cancer Research
  • National Institutes of Health (P50CA1270003)
  • National Cancer Institute (P50CA127003, P50CA1270003, R01CA133557, DP2CA195761, P01CA117969)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
autophagy, lysosomal biogenesis, pancreatic ductal adenocarcinoma, cancer metabolism, metabolic reprogramming, TFEB, TFE3, MITF, nuclear import, amino acid metabolism, cellular stress response, lysosomal catabolism
MeSH terms
Amino Acids, Animals, Autophagy, Energy Metabolism, Female, Homeostasis, Humans, Lysosomes, Neoplasm Transplantation, Pancreatic Neoplasms, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Carcinoma, Pancreatic Ductal, Active Transport, Cell Nucleus, Cell Line, Tumor, Mice, Microphthalmia-Associated Transcription Factor, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Heterografts

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