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:
  • 金额:
    $ 42.33万
  • 依托单位:
  • 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

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.
研究综述 异源三聚体G蛋白从G蛋白偶联受体(GPCR)发出信号, 调节多种生物过程的细胞表面蛋白质。Gα13是G12家族的一员 异源三聚体G蛋白,已被报道在不同的肿瘤背景下是肿瘤抑制剂或促进剂。 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。 胰腺癌的特征性遗传小鼠模型。从机制上讲,Gα13缺陷小鼠胰腺 肿瘤具有升高的mTOR信号传导,类似于人类胰腺癌。一致地,肿瘤来源于 Gα13缺陷型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 代谢和炎性细胞因子的表达。然而,肿瘤代谢的影响和 炎症对Gα13缺陷型肿瘤的发展和进展的影响以及mTOR信号转导是否 对这些过程的监管尚未进行调查。我们在本申请中的目的是阐明 胰腺癌细胞中Gα13缺失导致肿瘤发展的机制, 体内进展。核心假设是Gα13的缺失通过升高Gα13的水平促进肿瘤的发展。 mTOR信号传导驱动线粒体代谢和炎症。提出了两个具体目标: 确定mTORC 1信号传导是否是促进Gα13缺陷胰腺细胞代谢所必需的 肿瘤的2)确定mTORC1信号传导是否在介导Gα13细胞炎症增加中至关重要。 缺陷肿瘤在目标1中,我们将确定mTORC 1信号传导的抑制是否延迟肿瘤的发展 并诱导缺乏Gα13的早期和晚期肿瘤细胞死亡。此外,我们将评估Gα13损失 调节肿瘤代谢,Gα13缺陷型肿瘤是否易受线粒体 功能协调发展的在目标2中,我们将确定Gα13的缺失是否会增加炎症细胞因子水平和肿瘤发生。 促进早期和晚期肿瘤中的免疫细胞。我们将确定阻断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Gα13缺乏的肿瘤生长 肿瘤的最后,我们将研究是否联合抗炎药与线粒体的抑制剂, 功能将协同增强抗肿瘤功效。这项建议的创新之处是使用 一个独特的小鼠模型来研究Gα13的肿瘤抑制功能,其中两种基因中的基因缺失都是由于Gα13基因的缺失而引起的。 人类和小鼠胰腺肿瘤与mTOR信号升高和更差的生存结果相关。我们 还将使用人类肿瘤切片培养试验的创新方法来确定Gα13状态是否 决定了对mTORC 1信号传导抑制的反应。该提案意义重大,因为它将阐明 Gα13在胰腺癌中的肿瘤抑制机制,为胰腺癌的有益治疗提供了见解。 Gα13缺乏症。

项目成果

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