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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.

项目总结