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

• 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
• 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

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.

摘要 上皮向间充质转化(EMT)，与组织修复和修复有关的发育过程 病理过程，已被发现发生在癌症向侵袭性和 转移性疾病。积累的证据表明，EMT可能有助于 癌细胞的免疫抑制功能。然而，潜在的分子机制连接 EMT和免疫抑制在癌症中的作用在很大程度上仍不清楚。 为了解决这个问题，我们的研究小组开发了一种整合转录切割的方法来 乳腺癌细胞系与几种乳腺上皮细胞EMT的联合表达谱 模特们。该筛选鉴定了RNA结合基序单链相互作用蛋白3(RBMS3)为 与EMT显著且可重复地关联。我们进一步证明了RBMS3是稳定的 一组与EMT相关的基因，包括Prrx1。功能分析表明， RBMS3/Prrx1轴负责维持骨髓间充质的状态和运动特性 乳腺癌细胞，以及控制一组促炎细胞因子。更重要的是， 在TNBC MDA-MB231细胞中敲除RBMS3导致肿瘤形成显著延迟 活体，这在体外没有观察到。这些结果表明RBMS3介导乳腺癌 进展，潜在地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 RBMS3/Prrx1轴在免疫抑制和乳腺癌进展中的免疫活性 动物模型，并探讨靶向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，并产生两个关键结果：1) 通过对RBMS3/Prrx1轴的详细分析，揭示其在推动TNBC进展中的作用 免疫微环境的改变；2)靶向的概念验证证据 RBMS3/Prrx1轴将促进TNBC治疗的免疫治疗。这些结果将奠定坚实的基础 为进一步开发特异性靶向RBMS3/PRRX1轴治疗TNBC奠定了基础。 通过实现这些目标，我们将能够应对以下主要挑战：1)确定 为什么一些乳腺癌会成为危及生命的转移；以及2)消除或减少 与转移性乳腺癌相关的死亡率。