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Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism
Open accessAbstract
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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“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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“FOXO transcription factors, especially FOXO1 and FOXO3, also play critical roles in the regulation of autophagy gene expression [660, 913, 978].”
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Metadata
- 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
- ORCID
- Venue
- Nature
- Published
- 2015-07-13
- Volume
- 524
- Issue
- 7565
- Pages
- 361-365
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5086585
- 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
- FWCI
- 57.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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