title: Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma.
abstract: 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.
authors: Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, F-13009 Marseille, France.
authors: Fabienne
authors: F
authors: Guillaumond
authors: Julie
authors: J
authors: Leca
authors: Orianne
authors: O
authors: Olivares
authors: Marie-Noëlle
authors: MN
authors: Lavaut
authors: Nicolas
authors: N
authors: Vidal
authors: Patrice
authors: P
authors: Berthezène
authors: Nelson Javier
authors: NJ
authors: Dusetti
authors: Céline
authors: C
authors: Loncle
authors: Ezequiel
authors: E
authors: Calvo
authors: Olivier
authors: O
authors: Turrini
authors: Juan Lucio
authors: JL
authors: Iovanna
authors: Richard
authors: R
authors: Tomasini
authors: Sophie
authors: S
authors: Vasseur
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006595:Hexosamines / Q000096:biosynthesis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D006595:Hexosamines; D005973:Glutamine; D019344:Lactic Acid