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Targeting CXCL10 Chemokine Signaling in Breast Cancer Metastasis

靶向乳腺癌转移中的 CXCL10 趋化因子信号转导

基本信息

批准号：
10578007
负责人：
SUWON KIM
金额：
$ 7.68万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578007
关键词：
Attenuated Binding Biological Markers Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast cancer metastasis CRISPR/Cas technology CXCL10 gene Cell Line Cell Migration Induction Cell model Cells Clinical Trials Co-Immunoprecipitations Coupled Data Data Set Disease Disease-Free Survival Fatty acid glycerol esters Future GNB1 gene GTP-Binding Proteins Gene Deletion Gene Expression Genes Goals Grant Human Genome Immune Immune response Immunotherapy Implant In Vitro Inflammation Inflammatory Knowledge Laboratories Leukocytes Libraries Lung Malignant Neoplasms Mammary Neoplasms Maryland Mediating Metastasis Induction Metastatic Neoplasm to the Lung Metastatic breast cancer Migration Assay Modeling Molecular Mus Neoplasm Metastasis Oncogenic Pathway interactions Patient-Focused Outcomes Patients Positive Lymph Node Prognostic Marker Public Health Repression Research Role Signal Pathway Signal Transduction Site Specificity Testing Therapeutic Intervention Tumor Promotion Tumor Suppressor Proteins Tumor-infiltrating immune cells cancer cell cancer therapy cell motility chemokine clinically relevant cytotoxic gallein gene repression hormone receptor-negative improved inhibitor innovation malignant breast neoplasm mammary migration molecular subtypes mouse model neoplastic cell new therapeutic target novel novel therapeutics programs receptor relapse patients targeted treatment therapeutic target treatment response tumor tumor progression

项目摘要

Project Summary/Abstract Cxcl10 is a chemokine that mediates leukocyte migration during normal immune response. In cancers, Cxcl10 has been considered as a good prognostic marker correlated with tumor immune infiltrates and therapy response, consistent with its normal function in cytotoxic immune response. As such, Cxcl10 has been utilized as an indicator of robust immune response to therapy in clinical trials and Cxcl10-based cancer therapy has been proposed. Paradoxically, Cxcl10 is associated with metastasis and poor patient survival in several cancers including breast cancer, suggesting that Cxcl10 may have a function of promoting cancer progression. The molecular context of this Cxcl10 oncogenic role is not well understood. This research team has identified CXCL10 as one of the inflammatory genes repressed by the ING4 tumor suppressor, which suggested a potential inverse functional relationship. Preliminary studies from the PI’s laboratory analyzed breast tumor gene expression datasets including METABRIC and found that CXCL10-high/ING4-low expression was significantly associated with reduced disease-free survival in patients. These data suggested that Cxcl10 may exert an oncogenic effect in the context of ING4 deficiencies. Corroborating this, Cxcl10 induced in vitro migration of ING4-deleted cells, but not of ING4-intact cells. The use of inhibitors demonstrated that Cxcl10- induced cell migration required Cxcr3 (the receptor for Cxcl10) and the Gbg subunits downstream of Cxcr3 G protein-coupled protein receptor (GPCR), but not Gai. These data indicated a novel mechanism of the Cxcl10/Cxcr3/Gbg axis that mediated migration of ING4-deleted cells and potentially metastasis. Based on these data, the hypothesis that Cxcl10/Cxcr3/Gbg signaling mediates metastasis of ING4-deficient cancer was generated. The overall goal of the study is to unravel the mechanism of Cxcl10 oncogenic signaling. To test the hypothesis for this Small Grants Program R03 proposal, the specific aims will focus on Gbg signaling as it may present novel therapeutic opportunities. The specific aims are: 1) to identify the specific Gbg subunits responsible for mediating Cxcl10-induced migration of ING4-deleted breast cancer cells in vitro and 2) to determine the role of Gbg in Cxcl10-induced metastasis of mammary tumors using mouse models. In mouse models, gallein (a Gbg inhibitor) and Gb/Gg gene deletion will be evaluated for inhibitory effects on Cxcl10- induced tumor metastasis. Impact: Up to 34% of breast cancers have been identified as ING4-deficient, which is correlated with lymph node positivity and poor patient survival. Thus, delineation of the Cxcl10/Cxcr3/Gbg/ING4 signaling mechanism may have a broad impact on breast cancer treatment. If the proposed hypothesis is proven correct, the cell and mouse models in the study can further be used to test novel therapeutic agents targeting the pathway.

项目总结/摘要 cxcl 10是一种趋化因子，在正常免疫反应中介导白细胞迁移。在癌症中，Cxcl 10 已被认为是与肿瘤免疫浸润和治疗相关的良好预后标志物反应，与其在细胞毒性免疫反应中的正常功能一致。因此，Cxcl 10已被利用作为临床试验中对治疗的稳健免疫应答的指标，基于Cxcl 10的癌症治疗已经提出如特别地，在一些肿瘤中，Cxcl 10与转移和患者存活率差相关。包括乳腺癌在内的多种癌症中，提示Cxcl 10可能具有促进癌症进展的功能。这种Cxcl 10致癌作用的分子背景还不清楚。这个研究小组已经发现 CXCL 10是一种被ING 4肿瘤抑制基因抑制的炎症基因，这表明CXCL 10可能是一种肿瘤抑制基因。潜在的反函数关系PI实验室的初步研究分析了乳腺肿瘤包括METABRIC在内的基因表达数据集，发现CXCL 10-高/ING 4-低表达与患者无病生存率降低显著相关。这些数据表明，Cxcl 10可能在ING 4缺陷的情况下发挥致癌作用。证实了这一点，Cxcl 10在体外诱导 ING 4缺失细胞的迁移，而不是ING 4完整细胞的迁移。抑制剂的使用表明，Cxcl 10- 诱导的细胞迁移需要Cxcr 3（Cxcl 10的受体）和Cxcr 3 G下游的Gbg亚基蛋白偶联蛋白受体（GPCR），但不是Gai。这些数据表明了一种新的机制， Cxcl 10/Cxcr 3/Gbg轴介导ING 4缺失细胞的迁移和潜在转移。基于这些数据表明，Cxcl 10/Cxcr 3/Gbg信号转导介导ING 4缺陷型癌症转移的假设产生了。这项研究的总体目标是解开Cxcl 10致癌信号传导的机制。到为了检验这一小额赠款计划R 03提案的假设，具体目标将集中在千兆比特信号上因为它可能提供新的治疗机会。具体目标是：1）识别特定的Gbg 负责介导Cxcl 10诱导的ING 4缺失的乳腺癌细胞的体外迁移的亚基和2）使用小鼠模型确定Gbg在Cxc 110诱导的乳腺肿瘤转移中的作用。小鼠模型，gallein（一种Gbg抑制剂）和Gb/Gg基因缺失将评估对Cxcl 10的抑制作用。诱导肿瘤转移。影响：高达34%的乳腺癌被确定为ING 4缺陷，与淋巴结阳性和患者生存率低相关。因此，Cxcl 10/Cxcr 3/Gbg/ING 4的描绘信号传导机制可能对乳腺癌治疗产生广泛影响。如果假设被证明正确，研究中的细胞和小鼠模型可进一步用于测试靶向肿瘤的新型治疗剂。通路