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: 10565949
• 负责人: Pankaj Kumar Singh
• 金额: $ 62.77万
• 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/10565949
• 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; Invaded; Iron; Lipid Peroxidation; Lipids; Malignant neoplasm of pancreas; Mediating; Membrane Proteins; Metabolic stress; Metastatic/Recurrent; Mitochondria; Modeling; Molecular; Mus; Neoplasm Metastasis; Organelles; Outer Mitochondrial Membrane; Oxidative Stress; Pancreatic Ductal Adenocarcinoma; Pathologic; Patients; Pump; Regulation; Research; Resistance; Response Elements; Role; Signal Transduction; System; The Cancer Genome Atlas; Therapeutic; Xenograft Model; addiction; antiporter; 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.

该研究计划的目标是揭示线粒体 Ca2+ 信号传导的分子机制 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，利用转移性 PDAC 潜在治疗脆弱性的策略。 线粒体钙单向转运蛋白 (MCU) 是线粒体内膜上唯一的 Ca2+ 通道 负责线粒体 Ca2+ 的摄取。在某些病理条件下，MCU介导的线粒体 Ca2+ 超载导致细胞死亡。矛盾的是，MCU 水平在进展过程中显着增加 的几种类型的癌症。在本提案中，我们使用 PDAC 作为模型来研究其分子机制 MCU 控制癌症转移和进展。我们的数据表明 MCU 在 PDAC 中过度表达 通过 MCU-Nrf2 信号通路促进 PDAC 细胞迁移、侵袭和转移。通过非 通过有偏差的 RNA 测序和 TCGA 转录组数据集的询问，我们确定了 xCT（SLC7A11， 胱氨酸/谷氨酸逆向转运蛋白系统的功能亚基）作为 MCU 中潜在的药物靶标 介导的抗氧化反应和 PDAC 转移。有趣的是，MCU 过表达 PDAC 细胞是 沉迷于 xCT 介导的胱氨酸摄取。当 PDAC 细胞缺乏胱氨酸或用 xCT 处理时 抑制剂，MCU 促进铁死亡，这是一种脂质 ROS 介导的、铁依赖性调节细胞死亡的形式。瞄准1 我们将使用基因工程小鼠模型来研究MCU-Nrf2信号在PDAC转移中的作用 和进展。我们将确定 MCU 在目标 2 中激活 Nrf2 的机制并定义胱氨酸 成瘾作为目标 3 中 MCU 过表达 PDAC 的治疗脆弱性。该提案的成功将 为 PDAC 转移中线粒体钙信号转导提供重要的机制见解，并且可能 提供了预防 PDAC 转移复发的新途径。