Exploration of the immunosuppressive function of RBMS3/PRRX1 axis in TNBC

RBMS3/PRRX1轴在TNBC中免疫抑制功能的探讨

基本信息

批准号：
10650595
负责人：
Heather Marie Gibson
金额：
$ 18万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650595
关键词：
Address Animal Model Automobile Driving Biological Assay Bone Marrow Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Breast Epithelial Cells C57BL/6 Mouse Carcinoma Cells Chemotaxis Coculture Techniques Complex Contralateral Development Developmental Process Disease Expression Profiling Flow Cytometry Foundations Gene Targeting Genes Genetic Genetic Transcription Goals Homeobox Human Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Memory Immunosuppression Immunotherapeutic agent Immunotherapy Implant In Vitro Inbred BALB C Mice Infiltration Inflammation Inflammatory Intervention Life Link Literature MDA MB 231 Macrophage Malignant Neoplasms Mammary Neoplasms Mediating Mesenchymal Metastatic breast cancer Modeling Molecular Monitor Mus Neoplasm Metastasis Outcome Pathologic Processes Peripheral Phenotype Population Primary Neoplasm Prognosis Property Proteins RNA Binding RNA analysis Reproducibility Research Role Sampling Solid Techniques Testing Therapeutic Intervention Translating Tumor Immunity anti-CTLA4 anti-PD-1 breast cancer progression cancer cell cancer type cell motility chemokine cytokine effective therapy epithelial to mesenchymal transition exhaustion immune cell infiltrate immunological status immunosuppressed improved in vivo insight knock-down malignant breast neoplasm mortality mouse model next generation sequencing overexpression programs recruit response therapeutic target tissue repair transcriptome sequencing transcriptomics treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis

项目摘要

Abstract The epithelial to mesenchymal transition (EMT), a developmental process related to tissue repair and pathological processes, has been found to occur in the progression of carcinomas to invasive and metastatic disease. Accumulated evidence suggests the EMT could contribute to the immunosuppressive function of cancer cells. However, the underlying molecular mechanism linking EMT and immunosuppressive function in cancer remain largely unknown. To tackle this problem, our research group developed an integrative transcriptomic approach to combine expression profiling of breast cancer cell lines and several mammary epithelial cell EMT models. This screen identified RNA-binding motif single-stranded interacting protein 3 (RBMS3) as being significantly and reproducibly associated with EMT. We further showed that RBMS3 stabilized a group of EMT-related genes, including PRRX1. Functional analysis demonstrated the RBMS3/PRRX1 axis is responsible for maintaining mesenchymal status and motility properties of breast cancer cells, as well as controlling a group of pro- inflammatory cytokines. More importantly, knockdown of RBMS3 in TNBC MDA-MB231 cells results in a significant delay of tumorigenesis in vivo, which is not observed in vitro. These results indicate RBMS3 mediates breast cancer progression, potentially by simultaneously increasing invasive potential and promoting an immunosuppressed tumor microenvironment. In this study, we propose to investigate the effect of RBMS3/PRRX1 axis on immunosuppression and breast cancer progression in immunocompetent animal models and explore the potential impact of targeting RBMS3/PRRX1 axis in facilitating immunotherapy in TNBC models. We expect the proposed studies to be completed within two years, with two critical outcomes: 1) revealing the role of RBMS3/PRRX1 axis in driving TNBC progression through detailed analysis of the alterations of immune- microenvironment; 2) proof-of-concept evidence that targeting RBMS3/PRRX1 axis will facilitate immunotherapy for TNBC treatment. These results will lay a solid foundation for further development of specific targeting RBMS3/PRRX1axis for treatment of TNBC. By achieving these goals, we will be able to address the following overarching challenges: 1) identify why some breast cancers become life-threatening metastases; and 2) eliminate or reduce the mortality associated with metastatic breast cancer.

抽象的上皮到间质转化（EMT），一个与组织修复和相关的发育过程病理过程，已被发现发生在癌症进展为侵袭性和侵袭性的过程中。转移性疾病。积累的证据表明，急救医疗队可以有助于癌细胞的免疫抑制功能。然而，连接的潜在分子机制癌症中的 EMT 和免疫抑制功能仍然很大程度上未知。为了解决这个问题，我们的研究小组开发了一种综合转录组学方法结合乳腺癌细胞系和几种乳腺上皮细胞 EMT 的表达谱模型。该筛选将 RNA 结合基序单链相互作用蛋白 3 (RBMS3) 鉴定为与 EMT 显着且可重复相关。我们进一步表明 RBMS3 稳定一组 EMT 相关基因，包括 PRRX1。泛函分析证明了 RBMS3/PRRX1 轴负责维持间充质状态和运动特性乳腺癌细胞，以及控制一组促炎细胞因子。更重要的是， TNBC MDA-MB231 细胞中 RBMS3 的敲低导致肿瘤发生显着延迟体内，在体外未观察到。这些结果表明 RBMS3 介导乳腺癌进展，可能是通过同时增加侵袭潜力和促进免疫抑制的肿瘤微环境。在这项研究中，我们建议调查以下因素的影响： RBMS3/PRRX1 轴对免疫功能正常者的免疫抑制和乳腺癌进展的影响动物模型并探索靶向 RBMS3/PRRX1 轴在促进 TNBC 模型中的免疫治疗。我们预计拟议的研究将在两年内完成，并取得两个关键成果：1) 通过详细分析揭示 RBMS3/PRRX1 轴在驱动 TNBC 进展中的作用免疫微环境的改变； 2) 概念验证证据表明目标 RBMS3/PRRX1 轴将促进 TNBC 治疗的免疫疗法。这些成果将为为进一步开发用于治疗 TNBC 的特异性靶向 RBMS3/PRRX1axis 奠定了基础。通过实现这些目标，我们将能够应对以下首要挑战：1）确定为什么有些乳腺癌会发生危及生命的转移； 2）消除或减少与转移性乳腺癌相关的死亡率。