Mitochondrial calcium signaling in pancreatic cancer metastasis and progression

胰腺癌转移和进展中的线粒体钙信号传导

• 批准号: 10363987
• 负责人: Pankaj Kumar Singh
• 金额: $ 65.54万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363987
• 关键词: Antioxidants; Biguanides; Calcium Signaling; Cancer Control; Cell Death; Cell membrane; Cells; Cessation of life; Cystine; Data; Data Set; Depressed mood; Disease; Genes; Genetically Engineered Mouse; Glutamates; Glutathione; Goals; Inner mitochondrial membrane; Iron; Lipid Peroxidation; Lipids; Malignant neoplasm of pancreas; Mediating; Membrane Proteins; Metabolic stress; Mitochondria; Modeling; Molecular; Mus; Neoplasm Metastasis; Organelles; Outer Mitochondrial Membrane; Oxidative Stress; Pancreatic Ductal Adenocarcinoma; Pathologic; Patients; Pump; Recurrence; Regulation; Research; Resistance; Response Elements; Role; Signal Transduction; System; The Cancer Genome Atlas; Therapeutic; Xenograft Model; addiction; antiporter; base; calcium uniporter; cancer type; cell motility; chemotherapy; deprivation; druggable target; inhibitor; insight; mouse model; novel; novel strategies; overexpression; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; peroxidation; prevent; programs; recruit; response; success; transcriptome sequencing; transcriptomics; tumor progression; uptake

The goals of this research plan are to uncover the molecular mechanism by which mitochondrial Ca2+ signaling promotes pancreatic ductal adenocarcinoma (PDAC) cell migration, invasion and metastasis, and to devise novel strategies to exploit potential therapeutic vulnerability in metastatic PDAC based on our mechanistic studies. The Mitochondrial Calcium Uniporter (MCU) is the only Ca2+ channel on the mitochondrial inner membrane responsible for mitochondrial Ca2+ uptake. Under certain pathological conditions, MCU-mediated mitochondrial Ca2+ overload leads to cell death. Paradoxically, MCU levels are significantly increased during the progression of several types of cancer. In this proposal we use PDAC as a model to study the molecular mechanism by which MCU controls cancer metastasis and progression. Our data indicated that MCU overexpression in PDAC promotes PDAC cell migration, invasion and metastasis through a MCU-Nrf2 signaling circuit. Through non- biased RNA sequencing and interrogation of the TCGA transcriptomic datasets, we identified xCT (SLC7A11, the functional subunit of the cystine / glutamate antiporter system) as a potentially druggable target in MCU- mediated anti-oxidant response and PDAC metastasis. Intriguingly MCU overexpressing PDAC cells are addicted to xCT-mediated cystine uptake. When PDAC cells were deprived of cystine or treated with xCT inhibitors, MCU promotes ferroptosis, a form of lipid ROS-mediated, iron-dependent regulated cell death. In Aim1 we will use genetically engineered mouse model to investigate the role MCU-Nrf2 signaling in PDAC metastasis and progression. We will determine the mechanism by which MCU activates Nrf2 in Aim 2 and define cystine addiction as a therapeutic vulnerability in MCU overexpressing PDAC in Aim 3. The success of this proposal will provide important mechanistic insight for mitochondrial calcium signaling in PDAC metastasis, and will likely provide a novel avenue to prevent metastatic recurrence in PDAC.

本研究计划的目标是揭示线粒体Ca 2+信号转导的分子机制， 促进胰腺导管腺癌（PDAC）细胞迁移、侵袭和转移，并设计新的 基于我们的机制研究，我们提出了利用转移性PDAC的潜在治疗脆弱性的策略。 线粒体钙单向转运体（MCU）是线粒体内膜上唯一的钙离子通道 负责线粒体Ca 2+摄取。在某些病理条件下，MCU介导的线粒体 Ca 2+超载导致细胞死亡。巧合的是，MCU水平在进展过程中显着增加 几种类型的癌症。在这个建议中，我们使用PDAC作为模型来研究分子机制， MCU控制癌症转移和进展。我们的数据表明，在PDAC中MCU过表达 通过MCU-Nrf 2信号通路促进PDAC细胞迁移、侵袭和转移。通过非- 通过对TCGA转录组数据集的偏倚RNA测序和询问，我们鉴定了xCT（SLC 7A 11， 胱氨酸/谷氨酸反向转运蛋白系统的功能亚基）作为MCU中的潜在药物靶点- 介导的抗氧化反应和PDAC转移。有趣的是，MCU过度表达PDAC细胞， 对xCT介导的胱氨酸摄取上瘾。当PDAC细胞被剥夺胱氨酸或用xCT处理时， 抑制剂MCU促进铁细胞凋亡，这是一种脂质ROS介导的铁依赖性调节细胞死亡形式。目标1 我们将使用基因工程小鼠模型来研究MCU-Nrf 2信号在PDAC转移中的作用 和进步。我们将确定MCU激活Aim 2中Nrf 2的机制，并定义胱氨酸 成瘾是Aim 3中过表达PDAC的MCU的治疗弱点。这项提案的成功将 为PDAC转移中的线粒体钙信号传导提供了重要的机制见解，并可能 为预防PDAC的转移复发提供了新的途径。