Elucidating the mechanism of Ga13 mediated tumor suppression in pancreatic cancer

阐明 Ga13 介导的胰腺癌肿瘤抑制机制

基本信息

批准号：
10736355
负责人：
Mario Shields
金额：
$ 42.33万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736355
关键词：
Acceleration Anti-Inflammatory Agents Antibodies Biological Assay Biological Process Cancer Biology Cell Death Induction Cell Surface Proteins Cell physiology Cells Data Development Disease Exhibits FRAP1 gene Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Profiling Genes Genetic Genetic Engineering Heterotrimeric GTP-Binding Proteins Human Immune In Vitro Inflammation Inflammation Mediators Inflammatory Invaded KRAS oncogenesis Lymphoma Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator Metabolism Mitochondria Modeling Mus Mutation Myelogenous Myeloid-derived suppressor cells Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pancreatitis Patients Pharmaceutical Preparations Predisposition Process Proteins Publishing RNA Interference Regulation Reporting Research Role Signal Transduction Sirolimus Slice Specimen TP53 gene Testing Tumor Promoters Tumor Promotion Tumor Suppression Tumor Suppressor Proteins Tumor-Derived cancer cell cancer type cytokine drug development genetic signature immune cell infiltrate in vivo inhibitor innovation insight interest mRNA Expression mTOR Inhibitor member mitochondrial metabolism mouse model mutant neoplastic cell pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm patient stratification pyrimidine metabolism recruit response survival outcome therapeutic target therapy design tumor tumor growth tumor metabolism tumor progression

项目摘要

RESEARCH SUMMARY The heterotrimeric G proteins transduce signals from the G protein-coupled receptors (GPCRs), the largest class of cell surface proteins that regulate a wide variety of biological processes. Gα13, a member of the G12 family of heterotrimeric G proteins, has been reported to be a tumor suppressor or promoter in different tumor contexts. We recently reported that loss of Gα13 accelerated tumor development and reduced survival in a well- characterized genetic mouse model of pancreatic cancer. Mechanistically, Gα13-deficient mouse pancreatic tumors had elevated mTOR signaling, similar to human pancreatic cancer. Consistently, tumors derived from Gα13-deficient pancreatic cancer cells were susceptible to rapamycin, a well-characterized mTOR inhibitor. Recently, we have shown that loss of Gα13 in pancreatic tumors and cancer cells increased mitochondrial metabolism and expression of inflammatory cytokines. However, the impact of tumor metabolism and inflammation on the development and progression of Gα13-deficient tumors and whether mTOR signaling regulates these processes has not been investigated. Our objective in this application is to elucidate the mechanism(s) by which the deletion of Gα13 in the pancreas cancer cells contributes to tumor development and progression in vivo. The central hypothesis is that loss of Gα13 promotes tumor development through elevated mTOR signaling to drive mitochondrial metabolism and inflammation. Two specific aims are proposed: 1) Determine whether mTORC1 signaling is necessary for promoting cellular metabolism of Gα13-deficient pancreas tumors. 2) Determine whether mTORC1 signaling is essential in mediating the increased inflammation in Gα13- deficient tumors. In Aim 1, we will determine whether inhibition of mTORC1 signaling delays tumor development and induces cell death in early and advanced tumors lacking Gα13. Further, we will assess how Gα13 loss regulates tumor metabolism and whether Gα13-deficient tumors are susceptible to perturbations of mitochondrial functions. In Aim 2, we will determine whether Gα13 loss increases inflammatory cytokine levels and tumor- promoting immune cells in early and advanced tumors. We will determine whether blocking mTORC1 signaling limits the expression of candidate cytokines and immune cell infiltration to suppress tumor growth in Gα13 lacking tumors. Finally, we will examine whether combining anti-inflammatory agents with inhibitors of mitochondrial function will synergistically enhance anti-tumor efficacy. The innovative component of this proposal is the use of a unique mouse model to study the tumor suppressive function of Gα13, where the loss of the gene in both human and mouse pancreas tumors correlates with elevated mTOR signaling and worse survival outcome. We will also use the innovative approach of human tumor slice culture assays to determine whether Gα13 status dictates the response to inhibition of mTORC1 signaling. The proposal is significant because it will elucidate the tumor suppressive mechanisms of Gα13 in pancreatic cancer, providing insights into beneficial therapies for patients with Gα13 deficiency.

研究概要异三聚体 G 蛋白转导来自 G 蛋白偶联受体 (GPCR) 的信号，这是最大的一类 Gα13 是 G12 家族的成员，是调节多种生物过程的细胞表面蛋白。据报道，异三聚体 G 蛋白在不同的肿瘤环境中是肿瘤抑制因子或启动子。我们最近报道，Gα13 的缺失加速了肿瘤的发展并降低了良好的生存率。从机制上讲，Gα13 缺陷型小鼠胰腺癌的遗传小鼠模型具有特征性。肿瘤的 mTOR 信号传导增强，与人类胰腺癌相似。 Gα13 缺陷的胰腺癌细胞对雷帕霉素（一种充分表征的 mTOR 抑制剂）敏感。最近，我们发现胰腺肿瘤和癌细胞中 Gα13 的缺失增加了线粒体然而，肿瘤代谢和炎症细胞因子的表达的影响。炎症对 Gα13 缺陷型肿瘤的发生和进展的影响以及 mTOR 信号传导是否我们在此应用程序中的目的是阐明这些过程的规范。胰腺癌细胞中 Gα13 的缺失促进肿瘤发展的机制中心假设是 Gα13 的缺失通过升高促进肿瘤的发展。 mTOR 信号传导驱动线粒体代谢和炎症。提出了两个具体目标：1) 确定 mTORC1 信号传导对于促进 Gα13 缺陷型胰腺的细胞代谢是否是必需的 2) 确定 mTORC1 信号传导是否对于介导 Gα13- 炎症增加至关重要。在目标 1 中，我们将确定 mTORC1 信号传导的抑制是否会延迟肿瘤的发展。并在缺乏 Gα13 的早期和晚期肿瘤中诱导细胞死亡。此外，我们将评估 Gα13 损失的情况。调节肿瘤代谢以及 Gα13 缺陷型肿瘤是否容易受到线粒体扰动的影响在目标 2 中，我们将确定 Gα13 是否会增加炎症细胞因子水平和肿瘤的损失。我们将确定是否阻断 mTORC1 信号传导。限制候选细胞因子的表达和免疫细胞浸润，以抑制缺乏 Gα13 的肿瘤生长最后，我们将检查是否将抗炎药与线粒体抑制剂结合起来。功能将协同增强抗肿瘤功效。该提案的创新部分是使用研究 Gα13 肿瘤抑制功能的独特小鼠模型，其中两种基因均缺失人类和小鼠胰腺肿瘤与 mTOR 信号传导升高和较差的生存结果相关。还将使用人类肿瘤切片培养检测的创新方法来确定 Gα13 状态是否决定了对 mTORC1 信号传导抑制的反应该提议很重要，因为它将阐明 mTORC1 信号传导的反应。 Gα13 在胰腺癌中的肿瘤抑制机制，为胰腺癌的有益治疗提供见解 Gα13缺乏症患者。