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

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

Authors :
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
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)
Source :
EMBO Journal, EMBO Journal, 2022, ⟨10.15252/embj.2021110466⟩, The EMBO journal, vol 41, iss 9, EMBO J
Publication Year :
2022
Publisher :
HAL CCSD, 2022.

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.

Details

Language :
English
ISSN :
02614189 and 14602075
Database :
OpenAIRE
Journal :
EMBO Journal, EMBO Journal, 2022, ⟨10.15252/embj.2021110466⟩, The EMBO journal, vol 41, iss 9, EMBO J
Accession number :
edsair.doi.dedup.....402d390310382a7d2b9d332eef585cf9
Full Text :
https://doi.org/10.15252/embj.2021110466⟩