Galpha13 and pancreatic cancer progression

Galpha13 和胰腺癌进展

基本信息

批准号：
10377482
负责人：
Hidayatullah G. Munshi
金额：
$ 35.63万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377482
关键词：
3-Dimensional Attenuated Binding Proteins Cell-Cell Adhesion Cells Chemoresistance Collagen Collagen Type I Complex Data Development Distant Metastasis E-Cadherin Family Fibrosis Future Goals HMGA2 gene Health Heterotrimeric GTP-Binding Proteins Human Inflammation Inflammatory Innovative Therapy Knock-out Literature MMP14 gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Mission Modeling Neoplasm Metastasis Organoids Pancreatic Ductal Adenocarcinoma Patient-Focused Outcomes Patients Peptide Hydrolases Play Prognosis Public Health Reaction Research Research Support Role Signal Transduction Stem Cell Factor Testing Transgenic Organisms United States National Institutes of Health base cell motility chemotherapy discoidin domain receptor 1 expectation human disease improved in vivo innovation knock-down mast cell member mouse model novel novel strategies overexpression pancreatic ductal adenocarcinoma cell protease-activated receptor 3 recruit response targeted treatment tumor tumor progression

项目摘要

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.

最近的证据表明，3D 胶原蛋白中胰腺导管腺癌细胞 (PDAC) 的侵袭依赖于 Gα13，异源三聚体 G 蛋白 G12 家族的成员，并且可以通过胶原结合蛋白盘状蛋白结构域受体 1 (DDR1) 的长期目标是促进开发新的基于机制的靶向疗法来治疗 PDAC 的主要目标。该应用旨在确定 Gα13 如何促进体内 PDAC 进展。 Gα13 通过破坏 DDR1 介导的细胞粘附和激活 PDAC 来增强 PDAC 进展第二个假设是 Gα13 增强 PDAC 肿瘤中存在的炎症。这些假设基于大量初步数据，表明 Gα13 敲低会降低入侵 3D 胶原蛋白，减少 YAP1 信号传导，并增强 E-钙粘蛋白介导的细胞间粘附。此外，极性蛋白 Par3（可以在 DDR1 下游发挥作用）的丢失增强了 YAP1 信号传导并促进 3D 胶原中 PDAC 细胞的侵袭，此外，Gα13 还可以调节 HMGA2，从而介导。化疗耐药性，并且还调节 PDAC 细胞中的干细胞因子 (SCF)，它可以介导肥大细胞拟议研究的基本原理是确定影响和基础。 Gα13 在体内 PDAC 进展中的机制可能为继续研究提供强有力的理由开发 Gα13 及其下游效应子作为新型抗 PDAC 疗法的靶点。提出的目标是：1) 确定 Gα13 在体内 PDAC 进展中的作用；2) 确定 Gα13 的作用；介导体内 PDAC 炎症；3) 确定 DDR1 对抗 Gα13 的机制在第一个目标下，敲除 Gα13 对限制肿瘤进展和的作用。将在小鼠模型和人类 PDAC 类器官中评估对化疗反应的增强。 YAP1 在 Gα13 介导的 PDAC 进展中的作用以及 Gα13 介导化疗的机制对于第二个目标，将评估 PDAC 细胞中 Gα13 增强 SCF 的机制。此外，还将描述体内调节 Gα13 对肥大细胞迁移的影响。第三个目标是确定 Par3 在介导肿瘤中的作用。将评估小鼠模型和人类 PDAC 类器官中 Par3 的进展程度。 DDR1 下游减弱 Gα13 对 PDAC 进展影响的功能也将被确定。所提议的研究具有创新性，因为它利用了复杂的模型，包括 3D 腺泡培养、人类 PDAC 类器官以及转基因和原位小鼠模型，用于描述 Gα13 和 Par3 在 PDAC 进展的这项研究意义重大，因为它将提供以下机制的确定： Gα13 在介导肿瘤进展和化疗耐药以及 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。