Neurons release serine to support mRNA translation in pancreatic cancer
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.
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Neural invasion is a well-recognized feature of pancreatic tumors, and its severity negatively correlates with prognosis.
“Neural invasion is a well-recognized feature of pancreatic tumors, with the severity negatively correlating to prognosis262.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [262]
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References 86 · Cited by 292
- Authors
- Banh, R. S., Biancur, D. E., Yamamoto, K., Sohn, A. S. W., Walters, B., Kuljanin, M., Gikandi, A., Wang, H., Mancias, J. D., Schneider, R. J., Pacold, M. E., & Kimmelman, A. C.
- Affiliations
- NYU Langone Health (US)
- Dana-Farber Cancer Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kimmelman, Alec C.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 183
- Issue
- 5
- Pages
- 1202-1218.e25
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8100789
- OpenAlex
- W3096366814
- Cited by
- 292
- References
- 86
- Citations by year
- 2026: 58 · 2025: 64 · 2024: 43 · 2023: 47 · 2022: 46 · 2021: 29 · 2020: 5
- FWCI
- 11.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- V Foundation for Cancer Research (V2017-004)
- National Institute of General Medical Sciences (R01GM095567)
- American Cancer Society (RSG-13-298-01-TBG)
- Breast Cancer Research Foundation (BCRF-16-143)
- Damon Runyon Cancer Research Foundation (F99 CA245822, T32 CA009161, DRG-2348-18)
- Mary Kay Foundation (017-32)
- Burroughs Wellcome Fund
- National Cancer Institute (P30CA016087, F99 CA245822, T32 CA009161, PH719)
- Uehara Memorial Foundation
- Lustgarten Foundation
- Stanford Genome Technology Center
- Stand Up To Cancer
- National Institutes of Health (T32 CA9161-41)
- Hearst Foundations
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, serine, tumor innervation, mRNA translation, ribosome stalling, nerve growth factor, tumor microenvironment
- MeSH terms
- Adenocarcinoma, Aged, Animals, Axons, Codon, Female, Glycine, Humans, Male, Middle Aged, Mitochondria, Nerve Tissue, Neurons, Oxygen Consumption, Pancreatic Neoplasms, Pyrazoles, Pyrimidines, RNA, Messenger, RNA, Transfer, Serine, Protein Biosynthesis, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Proliferation, Mice, Rats
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