Dissecting Gut Microbiota Modulation on Brain Metastasis Progression

点击翻译按钮获取中文摘要

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.