Mitophagy in Tumor Microenvironment

摘要 有丝分裂吞噬是通过自噬选择性移除受损线粒体的过程。然而， 肿瘤微环境(TME)中的丝裂原吞噬作用仍不清楚。我们的初步数据表明，吞噬有丝分裂 在抑制胰腺肿瘤发生方面发挥了新的作用。使用自发的小鼠模型 胰腺癌，我们发现PINK1和PARK2这两个哺乳动物吞噬有丝分裂的核心介质的缺失 细胞，加速突变的Kras驱动的胰腺癌的发展。从机制上讲，有丝分裂缺陷 增加SLC25A37和SLC25A28依赖的线粒体铁积累，从而导致HIF1a- TME中依赖Warburg效应和AIM2依赖的炎性小体激活。AIM2炎症室- 介导的HMGB1释放进一步诱导免疫检查点蛋白CD274/PD-L1的表达。 因此，线粒体铁络合剂、抗HMGB1抗体或基因药物的给药 去除PINK1-/-和PARK2-/-小鼠的HIF1a或AIM2对突变的Kras驱动的胰腺具有保护作用 肿瘤发生学。重要的是，AIM2的高表达与胰腺癌患者的不良预后有关 癌症。这些令人兴奋的发现支持了我们的中心假设，即吞噬有丝分裂抑制胰腺 肿瘤发生通过控制线粒体铁依赖的TME。为了验证这一假设，我们将利用 分子、细胞和动物模型，以追求以下目标。目标1：确定有丝分裂吞噬的机制 缺乏介导的线粒体铁在TME中的积累。目标2.确定 线粒体铁蓄积介导的TME慢性炎症。目标3.确定 线粒体铁蓄积介导的TME免疫抑制。完成这些激动人心的 研究将揭示此前未被认识到的吞线体在调节线粒体铁中的作用 TME中的代谢，并建议将这些事件作为肿瘤治疗的靶点。

Abstract 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.