Dissecting Gut Microbiota Modulation on Brain Metastasis Progression

剖析肠道微生物群对脑转移进展的调节

• 批准号: 10687978
• 负责人: Samantha M Golomb
• 金额: $ 4.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687978
• 关键词: Affect; Antibiotic Therapy; Antibiotics; Antibodies; Antitumor Response; Astrocytes; Biological Assay; Brain; Brain Neoplasms; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Central Nervous System; Control Groups; Data; Development; Endothelial Cells; Environment; Etiology; Frequencies; Genetic Models; Histopathology; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunofluorescence Immunologic; Immunology procedure; Immunotherapy; In Situ; Incidence; Inflammatory; Inflammatory Response; Light; Malignant Neoplasms; Malignant neoplasm of lung; Mediator; Metastasis Suppression; Metastatic malignant neoplasm to brain; Microglia; Molecular; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Neurons; Peripheral; Phenotype; Play; Prevention strategy; Process; Proto-Oncogene Protein c-kit; Regulation; Role; Shapes; Signal Transduction; Signaling Molecule; Spatial Distribution; Stains; T cell differentiation; T-Cell Depletion; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Transgenic Mice; Transplantation; Tumor Promotion; Volatile Fatty Acids; anti-PD-L1 antibodies; brain behavior; brain remodeling; brain shape; brain tissue; cancer immunotherapy; cell type; clinical application; combinatorial; differential expression; dysbiosis; effector T cell; fatty acid supplementation; genetic signature; gut dysbiosis; gut microbiota; gut-brain axis; immune checkpoint blockade; improved; in vivo; insight; malignant breast neoplasm; melanoma; microbiota; mortality; mouse model; neoplastic cell; neutrophil; novel; patient prognosis; rational design; response; single cell analysis; treatment group; treatment strategy; tumor; tumor progression

Project Summary/Abstract Brain metastasis is the development of secondary tumors within brain tissue which are typically derived from melanoma, lung cancer, and breast cancer. The prognosis for patients with brain metastasis is devastatingly poor with a median survival of less than six months. To reduce brain metastasis incidence and cancer mortality, rationally-designed therapeutic approaches targeting the mechanistic underpinnings of brain metastasis progression is imperative. It is increasingly appreciated that the immune cells within the brain metastatic niche have indisputable and ubiquitous roles in regulating brain tumor progression. Yet, the regulation of CNS immunity by peripheral and systemic factors during brain metastatic colonization and outgrowth are not completely understood. The gut microbiota composition plays a crucial role in regulating the host’s peripheral immune system, correlates with anti-cancer immunotherapy efficacy and has a profound influence on brain behavior and function by reshaping the brain immune niche. In this study, we aim to identify how gut microbiota modulation reshapes the brain’s immune landscape and subsequently influences the metastatic niche and progression of brain metastasis. Antibiotic-induced gut microbiota dysbiosis led to a significant increase in brain metastasis burden in contrast to a vehicle-treated control group, suggesting that gut microbiota dysbiosis remodeled the brain metastatic niche to a tumor-promoting environment. Using single-cell analysis, we revealed compositional and transcriptional differences of immune cells within the brain metastatic niche of mice with and without gut dysbiosis. These findings suggest that gut dysbiosis affects specific immune cell types to promote brain metastasis outgrowth. Here, we propose to dissect the roles of these immune cell types in promoting brain metastasis outgrowth under gut dysbiosis conditions. Furthermore, we will elucidate the spatial distribution of effector immune cells within the brain metastatic niche and functional impact of gut-derived signaling molecules in brain metastasis outgrowth. Understanding the constituents and host-intrinsic regulators of the brain metastatic niche shaped through gut-brain communication will guide the development of novel and feasible brain metastasis prevention strategies through gut microbiota modulation.

项目摘要/摘要 脑转移是脑组织内继发性肿瘤的发展，通常起源于 黑色素瘤、肺癌和乳腺癌。脑转移患者的预后是毁灭性的。 中位生存期不到6个月的穷人。减少脑转移和癌症的发病率 死亡率，针对大脑机械基础的合理设计的治疗方法 转移进展势在必行。 人们越来越认识到，脑转移灶内的免疫细胞具有无可争辩的 在调节脑肿瘤进展中的普遍作用。然而，外周和外周对中枢神经系统免疫的调节 脑转移定植和生长过程中的全身性因素尚不完全清楚。胆量 微生物区系组成在调节宿主的外周免疫系统中起着至关重要的作用，与 抗癌免疫治疗疗效及通过重塑对大脑行为和功能的深刻影响 大脑免疫利基。在这项研究中，我们的目标是确定肠道微生物区系调制如何重塑大脑的 免疫格局和继而影响转移的生态位和脑转移的进展。 相比之下，抗生素诱导的肠道微生物区系失调导致脑转移负担显着增加 一组接受赋形剂治疗的对照组，表明肠道微生物区系失调重塑了脑转移 从利基到促进肿瘤的环境。使用单细胞分析，我们揭示了组成和 有肠道和无肠道小鼠脑转移瘤巢内免疫细胞的转录差异 生物失调。这些发现表明，肠道生物失调会影响特定免疫细胞类型，从而促进大脑 转移性生长。在这里，我们建议剖析这些免疫细胞类型在促进大脑发育中的作用。 转移是在肠道生物失调条件下发生的。此外，我们还将阐明 脑转移灶内效应免疫细胞及肠源性信号分子对功能的影响 在脑转移瘤中生长。了解大脑的组成成分和宿主内在调节 通过肠脑沟通形成的转移生态位将指导新的和可行的发展 通过肠道微生物区系调控预防脑转移的策略。