Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine cross-talk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal–cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer. Significance: This work identifies critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specific alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifically activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically. This article is highlighted in the In This Issue feature, p. 890
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Stellate cell-derived exosomes carry numerous metabolite and protein cargo, including amino acids, to pancreatic cancer cells.
“Stellate cell-derived exosomes have been shown to carry numerous metabolite and protein cargo to pancreatic cancer cells, including amino acids251,252.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [252]
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- Authors
- Parker, S. J., Amendola, C. R., Hollinshead, K. E. R., Yu, Q., Yamamoto, K., Encarnación-Rosado, J., Rose, R. E., LaRue, M. M., Sohn, A. S. W., Biancur, D. E., Paulo, J. A., Gygi, S. P., Jones, D. R., Wang, H., Philips, M. R., Bar-Sagi, D., Mancias, J. D., & Kimmelman, A. C.
- Affiliations
- NYU Langone Health (US)
- Dana-Farber Cancer Institute (US)
- New York University (US)
- 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
- Harvard University (US)
- The University of Texas MD Anderson Cancer Center (US)
- 2Perlmutter Cancer Center, New York University School of Medicine, New York, New York.
- Corresponding author
- Kimmelman, Alec C.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2020-07-01
- Volume
- 10
- Issue
- 7
- Pages
- 1018-1037
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC7334074
- OpenAlex
- W3019567338
- Cited by
- 175
- References
- 65
- Citations by year
- 2026: 20 · 2025: 22 · 2024: 24 · 2023: 45 · 2022: 31 · 2021: 20 · 2020: 13
- FWCI
- 11.59
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01CA157490, R01CA188048, P01CA117969, R35CA232124, R01GM095567, P30CA016087)
- ACS (RSG-13-298-01-TBG)
- Stand Up To Cancer (SU2C-AACR-DT26-17, R01GM132129, R01CA196941)
- NCI (F99CA245822)
- Uehara Memorial Foundation
- American Cancer Society (132942-PF-18-215-01-TBG)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, pancreatic stellate cells, alanine transport, SLC38A2, SLC1A4, neutral amino acid transporter, tumor microenvironment, alanine metabolism, tumor growth
- MeSH terms
- Adenocarcinoma, Alanine, Humans, Signal Transduction, Carcinoma, Pancreatic Ductal, Metabolic Networks and Pathways, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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