Biased chemokine receptor signaling in cancer progression

癌症进展中偏向的趋化因子受体信号传导

基本信息

批准号：
10077789
负责人：
Michael B Dwinell
金额：
$ 39.23万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077789
关键词：
Agonist Amino Acids Arrestins Binding Binding Sites Biochemical Biological Response Modifiers Biomimetics Bone Marrow Neoplasms CXCL12 gene CXCR4 Receptors CXCR4 gene Carcinoma Cell Culture Techniques Cell Death Cells Concept Formation Coupled Cytotoxic T-Lymphocytes Data Destinations Development Diagnosis Dimerization Disseminated Malignant Neoplasm Engineering Epithelial Cells Fostering G Protein-Coupled Receptor Signaling G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genetically Engineered Mouse Goals Growth Immune Immune Evasion Immunity Immunosuppression Immunotherapeutic agent Immunotherapy Infiltration Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Mediating Mediator of activation protein Modeling Molecular Conformation Movement Neoplasm Metastasis Nonmetastatic Normal Cell Operative Surgical Procedures Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Physiological Pre-Clinical Model Public Health Publishing Receptor Signaling Recurrence Reporting Research Residual Cancers Role Signal Pathway Signal Transduction Stromal Cells Structural Models Structure Survival Rate T-Lymphocyte Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Variant Work Xenograft Model anti-tumor immune response antitumor agent antitumor effect base beta-arrestin cancer cell cancer therapy cell killing chemokine chemokine receptor chemotherapy design dimer efficacy testing experimental study extracellular gemcitabine immune checkpoint blockade in vivo migration molecular imaging monomer mouse model mutant neoplastic cell novel novel strategies pancreatic cancer cells pancreatic cancer model pleiotropism pre-clinical prevent receptor spectroscopic imaging success synergism therapy resistant trafficking tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

Project Summary Pancreatic cancer is a uniformly lethal form of cancer with patients rarely surviving two years after diagnosis due to pronounced metastasis, immune suppression and evasion, desmoplasia, and unchecked tumor proliferation that together confer therapeutic resistance. Cancer metastatic potential is mediated by the G protein-coupled chemokine receptor CXCR4. The chemokine CXCL12 is the cognate ligand for CXCR4 and is an immune mediator produced by both stromal cells in the tumor microenvironment and normal cells at metastatic destinations. While a wealth of reports attribute elevated CXCR4 expression with pro-tumorigenic effects in numerous cancers, the precise mechanistic roles for CXCR4 and CXCL12 in non-metastatic pathways of pancreatic cancer progression remain poorly understood. Our published and exciting preliminary data have revealed a novel mechanism whereby CXCL12 can either promote or inhibit tumor progression and metastasis based on its ability to activate CXCR4 as a monomer or dimer. In pursuit of determining the mechanism behind CXCR4-mediated cancer progression, we have engineered a locked monomer variant of CXCL12 that acts as a balanced agonist at CXCR4, activating the entirety of its G protein and -arrestin signaling repertoire, as well as a locked dimer biased agonist variant which activates only a subset. We hypothesize that biased signaling at CXCR4 prevents tumor migration and progression while attracting cytotoxic T lymphocytes from the bone marrow and tumor periphery to infiltrate the tumor and kill cancer cells. The overall goal of this proposal is to harness biased agonist signaling as a multi-pronged anti-tumor approach to abrogate pancreatic cancer progression. Aim 1 will use genetically engineered mouse models of pancreatic cancer to analyze the in vivo influence of biased agonist signaling in tumor progression. Aim 2 will use transgenic mouse models and cell culture approaches to investigate the sparsely-studied effects of biased signaling on immune cell trafficking, infiltration, and tumor cell killing in the tumor microenvironment. Aim 3 will delve into the amino-acid level interactions between CXCL12 agonists with CXCR4 receptor to determine the mechanisms responsible for anti-tumor ligand biased and tissue biased signaling. The overall impact of the proposed work is that we will reveal a targetable structural and biochemical biased agonist signaling mechanism that explains the pleiotropic effects of CXCL12 and CXCR4 in cancer.

项目摘要胰腺癌是一种统一致命的癌症形式，患者很少在两年后生存由于明显的转移，免疫抑制和逃避，脱水症和诊断未检查的肿瘤增殖，共同会议治疗性抗性。癌症转移性潜力由G蛋白偶联的趋化因子受体CXCR4介导。趋化因子CXCL12是 cxcr4的同源配体，是肿瘤中两个基质细胞产生的免疫介质微环境和转移性目的地的正常细胞。虽然大量报告属性升高的CXCR4表达在许多癌症中具有促肿瘤作用，精度 CXCR4和CXCL12在胰腺癌的非转移途径中的机械作用进展仍然很少理解。我们发表的令人兴奋的初步数据显示了一个 CXCL12可以促进或抑制肿瘤进展和转移的新机制基于它将CXCR4激活为一个月或二聚体的能力。追求确定 CXCR4介导的癌症进展的机制，我们设计了一个锁定的单体 CXCL12的变体在CXCR4上充当平衡的激动剂，激活其全部G蛋白和-arrestin信号传导曲目，以及激活的锁定二聚体偏见的激动剂变体只有子集。我们假设CXCR4处有偏见的信号阻止肿瘤迁移和进展的同时吸引细胞毒性T淋巴细胞从骨髓和肿瘤周围到浸润肿瘤并杀死癌细胞。该提议的总体目标是利用偏见的激动剂信号传导是消除胰腺癌进展的多种抗肿瘤方法。目标1 将使用一般设计的胰腺癌的小鼠模型来分析体内影响肿瘤进展中的偏置激动剂信号传导。 AIM 2将使用转基因鼠标模型和单元格培养方法研究了偏见信号对免疫细胞的稀疏作用肿瘤微环境中的贩运，浸润和肿瘤细胞杀死。 AIM 3将深入研究 CXCL12激动剂与CXCR4受体之间的氨基酸水平相互作用，以确定负责抗肿瘤配体有偏见和组织偏置信号传导的机制。总体影响拟议的工作是，我们将揭示有目标的结构和生化偏见的激动剂信号传导机制解释了CXCL12和CXCR4在癌症中的多效作用。