Mitochondrial calcium signaling in pancreatic cancer metastasis and progression

这项研究计划的目标是揭示线粒体钙信号转导的分子机制 促进胰腺导管腺癌细胞的迁移、侵袭和转移，并设计出新的 基于我们的机制研究，开发转移性PDAC潜在治疗脆弱性的策略。 线粒体钙统一转运体(MCU)是线粒体内膜上唯一的钙通道 负责线粒体钙的摄取。在一定的病理条件下，MCU介导的线粒体 钙超载导致细胞死亡。矛盾的是，MCU水平在进展过程中显著增加 几种类型的癌症。在本方案中，我们使用PDAC作为模型来研究其分子机制。 MCU控制癌症的转移和进展。我们的数据表明，MCU在PDAC中过表达 通过MCU-Nrf2信号通路促进PDAC细胞的迁移、侵袭和转移。通过非 对TCGA转录数据集的有偏的RNA测序和询问，我们鉴定了XCT(SLC7A11， 半胱氨酸/谷氨酸逆向转运蛋白系统的功能亚基)作为MCU中潜在的可药物靶点- 介导的抗氧化反应与PDAC转移。有趣的是，MCU过度表达PDAC细胞 对XCT介导的半胱氨酸摄取上瘾。当PDAC细胞去除半胱氨酸或用XCT处理 抑制剂，MCU促进铁下垂，一种脂类ROS介导的铁依赖调节的细胞死亡形式。在Aim1 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 和进步。我们将确定MCU激活目标2中Nrf2的机制，并定义胱氨酸 成瘾是AIM 3中过度表达PDAC的MCU的治疗脆弱性。这项提议的成功将 为线粒体钙信号在PDAC转移中的作用提供了重要的机制洞察，并可能 为预防PDAC的转移复发提供了新的途径。

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.