1. Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression
- Author
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Gouirand, Victoire, Gicquel, Tristan, Lien, Evan C, Jaune‐Pons, Emilie, Da Costa, Quentin, Finetti, Pascal, Metay, Elodie, Duluc, Camille, Mayers, Jared R, Audebert, Stephane, Camoin, Luc, Borge, Laurence, Rubis, Marion, Leca, Julie, Nigri, Jeremy, Bertucci, François, Dusetti, Nelson, Iovanna, Juan Lucio, Tomasini, Richard, Bidaut, Ghislain, Guillaumond, Fabienne, Heiden, Matthew G Vander, and Vasseur, Sophie
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Rare Diseases ,Cancer ,Nutrition ,Digestive Diseases ,Pancreatic Cancer ,Aetiology ,2.1 Biological and endogenous factors ,3-Hydroxybutyric Acid ,Animals ,Ketone Bodies ,Mice ,Oxo-Acid-Lyases ,Pancreas ,Pancreatic Neoplasms ,HMGCL ,ketone bodies ,metastasis ,pancreatic cancer ,β-hydroxybutyrate ,Information and Computing Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.
- Published
- 2022