Dissecting Gut Microbiota Modulation on Brain Metastasis Progression

项目概要/摘要 脑转移瘤是脑组织内继发性肿瘤的发展，其通常来源于脑肿瘤。 黑色素瘤肺癌和乳腺癌脑转移瘤患者的预后令人担忧 中位生存期不到六个月的穷人。降低脑转移发病率和癌症 死亡率，合理设计的治疗方法，针对大脑的机械基础 转移进展是必要的。 越来越多的人认识到，脑转移瘤龛内的免疫细胞具有无可争议的， 普遍存在的调节脑肿瘤进展的作用。然而，外周和外周免疫对中枢免疫的调节 脑转移定植和生长过程中的全身因素尚未完全了解。肠道 微生物群组成在调节宿主的外周免疫系统中起着至关重要的作用， 抗癌免疫治疗的功效，并通过重塑大脑行为和功能产生深远的影响 大脑免疫生态位在这项研究中，我们的目标是确定肠道微生物群调节如何重塑大脑的 免疫景观，并随后影响脑转移瘤的转移生态位和进展。 抗生素诱导的肠道微生物群失调导致脑转移负荷显著增加， 与溶剂处理的对照组相比，表明肠道微生物群失调重塑了脑转移瘤。 一个促进肿瘤生长的环境。使用单细胞分析，我们揭示了组成和 有和没有肠的小鼠脑转移小生境内免疫细胞的转录差异 生态失调。这些发现表明，肠道生态失调会影响特定的免疫细胞类型， 转移生长在这里，我们建议剖析这些免疫细胞类型在促进大脑 在肠道生态失调条件下的转移生长。此外，我们还将阐明 脑转移瘤小生境内的效应免疫细胞和肠源性信号分子的功能影响 脑转移瘤的生长了解大脑的成分和宿主内在调节因子 通过肠-脑通信形成的转移性生态位将指导新的和可行的 通过肠道微生物群调节的脑转移预防策略。

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.