Galpha13 and pancreatic cancer progression

最近的证据表明，胰腺导管腺癌（PDAC）细胞在3D胶原蛋白中的侵袭 依赖于Gα13，G α 13是异源三聚体G蛋白G12家族的一员，并且可以被逆转。 胶原结合蛋白盘状结构域受体1（DDR 1）。长期目标是促进 开发用于治疗PDAC的新型机制靶向疗法。的主要目标 本申请旨在确定Gα13如何在体内促进PDAC进展。核心假设是 Gα13通过破坏DDR 1介导的细胞-细胞粘附和激活PDAC细胞的增殖， YAP 1信号。第二个假设是Gα13增强PDAC肿瘤中存在的炎症。 这些假设是基于大量的初步数据，表明Gα13敲低降低， 在3D胶原中的侵袭，减少YAP 1信号传导，并增强E-钙粘蛋白介导的细胞-细胞粘附。在 此外，极性蛋白Par 3的丧失，其可以在DDR 1下游发挥作用，增强YAP 1信号传导 并促进PDAC细胞在3D胶原中的侵袭。此外，Gα13调节HMGA 2，HMGA 2可以介导 在PDAC细胞中，干细胞因子（SCF）可介导肥大细胞增殖， 迁移拟议研究的基本原理是， Gα13在体内PDAC进展中的机制可能为继续研究PDAC提供了强有力的理由。 开发Gα13及其下游效应物作为新型抗PDAC治疗的靶点。三个具体 目的：1）确定Gα13在体内PDAC进展中的作用; 2）确定Gα 13在PDAC进展中的作用。 在体内介导PDAC炎症;和3）确定DDR 1抵消Gα13的机制 在PDAC细胞中。在第一个目标下，研究了敲除Gα13对限制肿瘤进展的作用， 将在小鼠模型和人PDAC类器官中评价对化疗的增加的反应。的 YAP 1在Gα13介导的PDAC进展中的作用以及Gα13介导化疗的机制。 将评估阻力。对于第二个目的，PDAC细胞中Gα13增强SCF的机制是 表达和肥大细胞迁移的特征。此外，体内调节Gα13对 还将测定其它炎性细胞。在第三个目标中，研究了Par 3在介导肿瘤生长中的作用。 将评价小鼠模型和人PDAC类器官中的进展。第三部分 还将确定DDR 1下游减弱Gα13对PDAC进展的作用的功能。 这项研究是创新的，因为它利用了复杂的模型，包括3D腺泡文化，人类 PDAC类器官以及转基因和原位小鼠模型，以描述Gα13和Par 3在PDAC类器官中的作用。 PDAC进展。这项拟议的研究是重要的，因为它将提供一个机械确定 Gα13在介导肿瘤进展和化疗耐药性以及PDAC炎症中的作用， 随后为开发治疗PDAC患者的创新疗法创造了新的机会。

Recent evidence indicates that invasion of pancreatic ductal adenocarcinoma (PDAC) cells in 3D collagen depends on Gα13, a member of the G12 family of heterotrimeric G proteins, and can be reversed by the collagen-binding protein discoidin domain receptor 1 (DDR1). The long-term goal is to contribute toward the development of novel mechanism-based targeted therapies for the treatment of PDAC. The main objective in this application is to determine how Gα13 contributes to PDAC progression in vivo. The central hypothesis is that Gα13 enhances PDAC progression by disrupting DDR1-mediated cell-cell adhesion and by activating YAP1 signaling. A second hypothesis is that Gα13 enhances inflammation that is present in PDAC tumors. These hypotheses are based on extensive preliminary data demonstrating that Gα13 knockdown decreases invasion in 3D collagen, decreases YAP1 signaling, and enhances E-cadherin-mediated cell-cell adhesion. In addition, loss of the polarity protein Par3, which can function downstream of DDR1, enhances YAP1 signaling and promotes invasion of PDAC cells in 3D collagen. Moreover, Gα13 regulates HMGA2, which can mediate chemoresistance, and also regulates in PDAC cells stem cell factor (SCF), which can mediate mast cell migration. The rationale for the proposed research is that a determination of the effect and underlying mechanism of Gα13 in PDAC progression in vivo is likely to provide strong justification for the continued development of Gα13 and its downstream effectors as targets for novel anti-PDAC therapy. Three specific aims are proposed: 1) Determine the role of Gα13 in PDAC progression in vivo; 2) Determine the role of Gα13 in mediating PDAC inflammation in vivo; and 3) Determine the mechanism by which DDR1 counteracts Gα13 in PDAC cells in vivo. Under the first aim, the effects of knocking out Gα13 on limiting tumor progression and increasing response to chemotherapy will be evaluated in mouse models and in human PDAC organoids. The role of YAP1 in Gα13-mediated PDAC progression and the mechanism by which Gα13 mediates chemo- resistance will be evaluated. For the second aim, the mechanism by which Gα13 in PDAC cells enhances SCF expression and mast cell migration will be characterized. In addition, the effects of modulating Gα13 in vivo on other inflammatory cells will also be determined. In the third aim, the role of Par3 in mediating tumor progression in mouse models and in human PDAC organoids will be evaluated. The extent to which Par3 functions downstream of DDR1 to attenuate the effects of Gα13 on PDAC progression will also be determined. The research proposed is innovative because it utilizes complex models, including 3D acinar cultures, human PDAC organoids, and transgenic and orthotopic mouse models, to delineate the role of Gα13 and Par3 in PDAC progression. This proposed research is significant because it will provide a mechanistic determination of the role of Gα13 in mediating tumor progression and chemoresistance, and also PDAC inflammation, subsequently creating new opportunities for the development of innovative therapies to treat PDAC patients.