Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment.
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Autophagy in stromal fibroblasts can generate alanine, which is subsequently used by PDAC cells to fuel the TCA cycle.
“Autophagy in stromal fibroblasts can generate alanine, which is subsequently used by pancreatic ductal adenocarcinoma (PDAC) cells to fuel the tricarboxylic acid (TCA) cycle126,130,131.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [130]
Cancer cells and post-mitotic cells have completely different metabolism despite both being energy-demanding, which may explain why NAD+ augmentation and autophagy can be neuroprotective yet promote specific cancers such as pancreatic cancer.
“cancer cells and post-mitotic cells exhibit a completely different metabolism, which may explain why the neuroprotective conditions of NAD+ augmentation and autophagy (Sousa et al., 2016) can also promote the growth of specific cancers (e.g., pancreatic cancer).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Sousa et al., 2016
Pancreatic ductal adenocarcinoma cells can consume alanine produced by pancreatic stellate cells in vitro, and the secreted alanine appears to help promote tumor cell proliferation and survival under nutrient-limited conditions.
“Pancreatic ductal adenocarcinoma cells can consume alanine produced by pancreatic stellate cells in vitro, and the secreted alanine appears to help promote tumor cell proliferation and survival under nutrient-limited conditions (Sousa et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Sousa et al., 2016
CAFs provide signals that promote epigenetic and metabolic rewiring of cancer cell metabolism.
“CAFs provide signals that promote epigenetic and metabolic re-wiring of cancer cell metabolism247.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [247]
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- Authors
- Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., Kremer, D., Hwang, R. F., Witkiewicz, A. K., Ying, H., Asara, J. M., Evans, R. M., Cantley, L. C., Lyssiotis, C. A., & Kimmelman, A. C.
- Affiliations
- Harvard University (US)
- University of Michigan (US)
- Salk Institute for Biological Studies (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Beth Israel Deaconess Medical Center (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Lyssiotis, Costas A.
- Kimmelman, Alec C.
- ORCID
- Venue
- Nature
- Published
- 2016-08-10
- Volume
- 536
- Issue
- 7617
- Pages
- 479-483
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5228623
- OpenAlex
- W2516006356
- Cited by
- 1,122
- References
- 30
- Citations by year
- 2026: 93 · 2025: 85 · 2024: 96 · 2023: 113 · 2022: 129 · 2021: 165 · 2020: 132 · 2019: 108 · 2018: 93 · 2017: 84 · 2016: 23
- FWCI
- 55.56
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-10-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od010612-01)
- National Cancer Institute (R00CA188259, R01CA188048, R01CA157490, P01CA120964, P30CA046592, T32CA009370, P30CA014195, P01CA117969, P30CA006516, 5-P30 CA06516)
- National Institute of General Medical Sciences (R01GM095567, GM095567)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK-097153, U24DK097153)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- pancreatic stellate cells, pancreatic ductal adenocarcinoma, tumor microenvironment, autophagy, non-essential amino acids, cancer metabolism, TCA cycle, lipogenesis, hypoxia, alternative carbon sources
- MeSH terms
- Adenocarcinoma, Alanine, Animals, Autophagy, Carbon, Citric Acid Cycle, Female, Glucose, Humans, Neoplasm Transplantation, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Mice, Biosynthetic Pathways, Pancreatic Stellate Cells, Tumor Microenvironment, Heterografts
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