Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression

Autor: Victoire Gouirand, Tristan Gicquel, Evan C Lien, Emilie Jaune‐Pons, Quentin Da Costa, Pascal Finetti, Elodie Metay, Camille Duluc, Jared R Mayers, Stephane Audebert, Luc Camoin, Laurence Borge, Marion Rubis, Julie Leca, Jeremy Nigri, François Bertucci, Nelson Dusetti, Juan Lucio Iovanna, Richard Tomasini, Ghislain Bidaut, Fabienne Guillaumond, Matthew G Vander Heiden, Sophie Vasseur
Přispěvatelé: Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Institut Paoli-Calmettes, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Koch Institute for Integrative Cancer Research at MIT [Cambridge, MA], Massachusetts Institute of Technology (MIT)
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: EMBO Journal
EMBO Journal, 2022, ⟨10.15252/embj.2021110466⟩
The EMBO journal, vol 41, iss 9
EMBO J
ISSN: 0261-4189
1460-2075
DOI: 10.15252/embj.2021110466⟩
Popis: 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.
Databáze: OpenAIRE
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