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Mitophagy in Tumor Microenvironment

肿瘤微环境中的线粒体自噬

基本信息

批准号：
10675423
负责人：
Daolin Tang
金额：
$ 38.12万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675423
关键词：
Acceleration Adaptor Signaling Protein Animal Model Antibodies Autophagocytosis Cell model Cells Chronic Data Development Event Excision FDA approved Genetic HIF1A gene HMGB1 gene Human Hydroxychloroquine Immune Immunosuppression Inflammasome Inflammation Inflammatory Response Iron Iron Chelation Knock-out Malignant neoplasm of pancreas Mammalian Cell Mediating Mediator Mitochondria Modeling Molecular Mus PARK2 gene PINK1 gene Paclitaxel Pathologic Pathway interactions Patients Pharmaceutical Preparations Play Post-Translational Protein Processing Process Prognosis Proteins Regulation Role STAT1 gene Signal Transduction Signaling Protein Testing Up-Regulation Warburg Effect anti-cancer cancer type chemotherapy gemcitabine immune checkpoint improved in vivo iron metabolism molecular modeling mouse model mutant novel pancreatic cancer patients pancreatic neoplasm pancreatic tumorigenesis pharmacologic programmed cell death ligand 1 protein degradation tumor tumor initiation tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis

项目摘要

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.

摘要

项目成果

期刊论文数量（81）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The ferroptosis inducer erastin promotes proliferation and differentiation in human peripheral blood mononuclear cells.

铁死亡诱导剂erastin促进人外周血单个核细胞增殖和分化

DOI：
10.1016/j.bbrc.2018.07.100
发表时间：
2018-09-10
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Wang D;Xie N;Gao W;Kang R;Tang D
通讯作者：
Tang D

Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies.

DOI：
10.1245/s10434-020-09477-4
发表时间：
2021-05
期刊：
Annals of surgical oncology
影响因子：
3.7
作者：
Ekeke CN;Russell KL;Joubert K;Bartlett DL;Luketich JD;Soloff AC;Guo ZS;Lotze MT;Dhupar R
通讯作者：
Dhupar R

The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation.