Journal
DEVELOPMENTAL CELL
Volume 46, Issue 4, Pages 441-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2018.07.012
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Funding
- US National Institutes of Health [R01GM115366, R01CA160417, R01GM053396, R01CA211070, R01CA181450]
- American Cancer Society [RSG-16-014-01-CDD]
- Natural Science Foundation of Guangdong Province [2016A030308011]
- National Natural Science Foundation of China [31671435, 81400132, 81772508]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme
- Lin He's Academician Workstation of New Medicine and Clinical Translation
- International Scientific and Technology Cooperation Program of China [2015DFA31490]
- Ligue Contre le Cancer (equipe labelisee)
- Agence National de la Recherche (ANR)- Projets blancs
- ANR
- ERA-Net for Research on Rare Diseases
- Association pour la Recherche sur le Cancer (ARC)
- Canceropole Ile-de-France
- Institut National Du Cancer (INCa)
- Institut Universitaire de France
- Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Council (ERC)
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- [P30CA047904]
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Pancreatic cancer is an aggressive malignancy with changes in the tumor microenvironment. Here, we demonstrate that PINK1 and PARK2 suppressed pancreatic tumorigenesis through control of mitochondrial iron-dependent immunometabolism. Using mouse models of spontaneous pancreatic cancer, we show that depletion of Pink1 and Park2 accelerates mutant Kras-driven pancreatic tumorigenesis. PINK1-PARK2 pathway-mediated degradation of SLC25A37 and SLC25A28 increases mitochondrial iron accumulation, which leads to the HIF1A-dependent Warburg effect and AIM2-dependent inflammasome activation in tumor cells. AIM2-mediatedHMGB1 release further induces expression of CD274/PD-L1. Consequently, pharmacological administration of mitochondrial iron chelator, anti-HMGB1 antibody, or genetic depletion of Hif1a or Aim2 in pink1(-/-)and park2(-/-)mice confers protection against pancreatic tumorigenesis. Low PARK2 expression and high SLC25A37 and AIM2 expression are associated with poor prognosis in patients with pancreatic cancer. These findings suggest that disrupted mitochondrial iron homeostasis may contribute to cancer development and hence constitute a target for therapeutic intervention.
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