Mitophagy is the process of selective removal of damaged mitochondria via autophagy. However, the impact of mitophagy in the tumor microenvironment (TME) remains unclear. Our preliminary data suggest that mitophagy plays a novel role in the suppression of pancreatic tumorigenesis. Using mouse models of spontaneous pancreatic cancer, we show that depletion of Pink1 and Park2, two core mediators of mitophagy in mammalian cells, accelerates mutant Kras-driven pancreatic cancer development. Mechanistically, mitophagy deficiency increases SLC25A37- and SLC25A28-dependent mitochondrial iron accumulation, which leads to the HIF1A- dependent Warburg effect and AIM2-dependent inflammasome activation in the TME.
AIM2 inflammasome- mediated HMGB1 release further induces expression of the immune checkpoint protein 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 mutant Kras-driven pancreatic tumorigenesis. Importantly, high AIM2 expression is associated with poor prognosis in patients with pancreatic cancer. These exciting findings support our central hypothesis that mitophagy suppresses pancreatic tumorigenesis through control of the mitochondrial iron-dependent TME. To test this hypothesis, we will exploit molecular, cellular, and animal models to pursue the following aims.
Aim 1 : Identify the mechanisms of mitophagy deficiency-mediated mitochondrial iron accumulation in the TME.
Aim 2. Identify the mechanisms of mitochondrial iron accumulation-mediated chronic inflammation in the TME.
Aim 3. Identify the mechanisms of mitochondrial iron accumulation-mediated immunosuppression in the TME. The completion of these exciting studies will uncover a previously underappreciated role for mitophagy in modulating mitochondrial iron metabolism in the TME and suggest targeting these events for tumor therapy.
Pancreatic cancer remains one of the deadliest cancer types with limited treatment options; therefore, identification of targetable key players in tumor initiation and progression is urgently needed. We postulate that mitophagy suppresses pancreatic tumorigenesis through the control of the mitochondrial iron-dependent tumor microenvironment. Our proposal will uncover a previously underappreciated role for mitophagy in the tumor microenvironment and suggest targeting these events for tumor therapy.
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