Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma
Open accessAbstract
Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the “glycolytic” switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.
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Analysis of nutrients in murine tumor interstitial fluid shows a profile within pancreatic tumors that is starkly different from serum levels.
“analysis of the nutrients available within murine tumor interstitial fluid demonstrates a starkly different profile within pancreatic tumors vs. serum levels194”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [194]
The disparity between nutrient availability in the pancreatic TME, the bloodstream, and secondary organs colonized in metastasis allows for varied metabolic states for PDAC cells.
“The disparity between nutrient availability imposed by the pancreatic TME, the bloodstream and other routes of dissemination, and secondary organs colonized in metastasis allow for varied metabolic states for PDAC cells194.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [194]
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- ACKNOWLEDGMENTS. We thank the cell culture platform and the mice colony facility (Cell stress, Unité 1068) for technical assistance as well as JeanPierre Cavaille for glucose and lactate measurements. Samples of human origin were obtained from the IPC/CRCM Tumour Bank (authorization no. AC-2007-33), granted by the French Ministry of Research. The project was approved by the IPC Institutional Review Board. This work was supported in part by grants from the National Institut of Cancer, Cancéropôle ProvenceAlpes-Côte d ' Azur, and the Ligue contre le Cancer. F.G. was supported by Fondation Santé, Sport et Développement Durable and Fondation de France fellowships.
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- Authors
- Guillaumond, F., Leca, J., Olivares, O., Lavaut, M.-N., Vidal, N., Berthezène, P., Dusetti, N. J., Loncle, C., Calvo, E., Turrini, O., Iovanna, J. L., Tomasini, R., & Vasseur, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, F-13009 Marseille, France;
- Centre hospitalier de l'Université Laval (CA)
- Institut Paoli-Calmettes (IPC), F-13009 Marseille, France;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-02-13
- Volume
- 110
- Issue
- 10
- Pages
- 3919-3924
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3593894
- OpenAlex
- W2149828028
- Cited by
- 413
- References
- 28
- Citations by year
- 2026: 23 · 2025: 12 · 2024: 33 · 2023: 32 · 2022: 41 · 2021: 45 · 2020: 35 · 2019: 27 · 2018: 33 · 2017: 38 · 2016: 27 · 2015: 34 · 2014: 24 · 2013: 9
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- pancreatic ductal adenocarcinoma, tumor hypoxia, glycolysis, hexosamine biosynthetic pathway, O-GlcNAc, glutamine metabolism, epithelial-mesenchymal transition, lactate efflux, oxidative phosphorylation, tumor aggressiveness, tumor cell survival, tumor microenvironment
- MeSH terms
- Animals, Hypoxia, Cell Survival, Disease Models, Animal, Glutamine, Glycolysis, Hexosamines, Humans, Male, Mice, Nude, Mice, Transgenic, Models, Biological, Pancreatic Neoplasms, Transplantation, Heterologous, Cell Hypoxia, Lactic Acid, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Metabolic Networks and Pathways
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