Journal
CELL REPORTS MEDICINE
Volume 1, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2020.100143
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Funding
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- Institut National Du Cancer (INCa)
- Fondation ARC pour la Recherche sur le Cancer [PJA 20151203544]
- La Ligue Nationale contre le Cancer (LNCC)
- DGOS (labelization SIRIC)
- Fondation Amidex
- Fondation de France
- Canceropole Provence-Alpes-Cote d'Azur (PACA)
- Federation GEFLUC
- Fondation ARC pour la Recherche sur le Cancer
- Fondation pour la Recherche Medicale
- CONACYT (Mexico) [339091/471717]
- IMODI
- Association Azm et Saade
- French Agence Nationale de la Recherche
- Canceropole PACA
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Mitochondrial respiration (oxidative phosphorylation, OXPHOS) is an emerging target in currently refractory cancers such as pancreatic ductal adenocarcinoma (PDAC). However, the variability of energetic metabolic adaptations between PDAC patients has not been assessed in functional investigations. In this work, we demonstrate that OXPHOS rates are highly heterogeneous between patient tumors, and that high OXPHOS tumors are enriched in mitochondrial respiratory complex I at protein and mRNA levels. Therefore, we treated PDAC cells with phenformin (complex I inhibitor) in combination with standard chemotherapy (gemcitabine), showing that this treatment is synergistic specifically in high OXPHOS cells. Furthermore, phenformin cooperates with gemcitabine in high OXPHOS tumors in two orthotopic mouse models (xenografts and syngeneic allografts). In conclusion, this work proposes a strategy to identify PDAC patients likely to respond to the targeting of mitochondrial energetic metabolism in combination with chemotherapy, and that phenformin should be clinically tested in appropriate PDAC patient subpopulations.
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