Prevention of Brain Metastasis Relapse through Modulation of Age-related Gut Microbiota-Immune Cross talk

项目摘要 转移是癌症死亡的主要原因，其中脑转移是最具侵袭性和 无法治愈的转移性复发。乳腺癌脑转移患者的预后是 极度贫穷，中位生存期不到六个月。脑转移瘤复发取决于 播散性肿瘤细胞与脑转移微环境成分之间复杂的相互作用 -利基市场。为了抗击乳腺癌死亡率，必须制定合理设计的战略，以 防止脑转移复发。 免疫系统在调节原发和转移肿瘤方面起着重要作用。胆量 微生物区系--始终由共生、共生和致病微生物组成的生态群落 启动并重塑衰老过程中的免疫监视系统。神经科学中越来越多的证据 菲尔德证明了肠道微生物区系失调和脑部炎症以及 各种神经系统疾病。由于脑转移复发通常发生在老年乳腺癌幸存者中，在这方面 拟议的研究，我们将重点描述微生物区系与宿主免疫相互作用的机制 影响老年女性人口的转移进展。我们假设与年龄相关的肠道生物失调 可能重塑脑免疫转移的生态位，从而影响脑转移复发。我们的首要目标 就是剖析肠道生物失调和脑转移复发之间的机制联系，并确定 为老年乳腺癌幸存者量身定做的预防脑部疾病的临床可操作益生菌调节策略 转移性复发。基于成熟的衰老模型、尖端单细胞基因组学和 元基因组学方法，我们将用肠道微生物区系检测脑转移瘤的分子变化。 年迈的寄主的变化。然后设计和测试有针对性的微生物区系调节策略来预防大脑 老年宿主的转移性复发。 这个项目是首次尝试探索肠道微生物区系和乳房之间的机械联系。 在老龄化背景下癌症脑转移的利基。从癌症预防的角度来看，机械论 通过研究年龄相关的生物失调调节脑转移复发的见解将指导个性化 为每个乳腺癌幸存者量身定做的微生物区系调制策略，以防止致命的脑部 转移性复发。

Project Summary Metastasis is the major cause of cancer mortality, with brain metastasis being the most aggressive and incurable form of metastatic recurrence. The prognosis for breast cancer patients with brain metastasis is devastatingly poor with a median survival of less than six months. Brain metastasis relapse depends on the intricate interplay between disseminated tumor cells and components of the brain metastatic microenvironment - the niche. To combat breast cancer mortality, it is imperative to develop rationally-designed strategies to prevent brain metastasis relapse. The immune system plays a significant role in regulating both primary and metastatic tumors. The gut microbiota - an ecological community of commensal, symbiotic, and pathogenic microorganisms consistently primes and reshapes the immune surveillance system during aging. Mounting evidence in the neuroscience field demonstrated a clear connection between gut microbiota dysbiosis and brain inflammation as well as various neurological diseases. As brain metastasis relapse often occurs in aged breast cancer survivors, in this proposed study, we will focus on delineating mechanisms by which the microbiota-host immune interaction influences metastatic progression in the aged female population. We postulate that age-related gut dysbiosis may reshape the brain immune metastatic niche to influence brain metastatic relapse. Our overarching goal is to dissect the mechanistic connection between gut dysbiosis and brain metastasis relapse and identify clinically actionable probiotics modulation strategies tailored to aged breast cancer survivors to prevent brain metastatic relapse. Based on well-established aging models, cutting-edge single-cell genomics, and metagenomics approaches, we will examine molecular changes in brain metastatic tumors with gut microbiota alterations in the aged host. Then design and test targeted microbiota-modulation strategies to prevent brain metastatic relapse in aged hosts. This project is the first attempt to explore the mechanistic link between the gut microbiota and breast cancer brain metastatic niche in the aging context. From the cancer prevention perspective, mechanistic insights via examining age-associated dysbiosis in regulating brain metastasis relapse will guide personalized microbiota-modulation strategy that is tailored to each breast cancer survivor to prevent deadly brain metastatic relapse.