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的， 无法治愈的转移性复发。乳腺癌脑转移患者的预后是 中位生存期不到六个月的患者非常可怜。脑转移复发取决于 播散性肿瘤细胞和脑转移微环境成分之间的复杂相互作用 - niche为了降低乳腺癌死亡率，必须制定合理设计的策略， 预防脑转移复发。 免疫系统在调节原发性和转移性肿瘤中起重要作用。肠道 微生物群-一个生态群落的共生，共生和病原微生物一致 在衰老过程中启动和重塑免疫监视系统。神经科学中越来越多的证据 研究表明，肠道微生物群失调与大脑炎症之间存在明确的联系， 各种神经系统疾病。由于脑转移复发经常发生在老年乳腺癌幸存者中， 建议的研究，我们将集中在描绘的机制，微生物-宿主免疫相互作用 影响老年女性人群的转移进展。我们假设年龄相关的肠道生态失调 可能重塑脑转移瘤的免疫生态位，影响脑转移瘤复发。我们的总目标 是剖析肠道生态失调和脑转移复发之间的机制联系， 为老年乳腺癌幸存者量身定制的临床可行的益生菌调节策略，以预防脑 转移性复发基于成熟的衰老模型，尖端的单细胞基因组学， 宏基因组学方法，我们将研究脑转移瘤与肠道微生物群的分子变化 老年人的变化然后设计和测试有针对性的微生物群调节策略， 老年宿主的转移复发。 该项目首次尝试探索肠道微生物群与乳腺癌之间的机制联系。 癌症脑转移在老龄化背景下的小生境。从预防癌症的角度来看， 通过检查与年龄相关的生态失调在调节脑转移复发中的见解将指导个性化治疗。 微生物群调节策略，为每个乳腺癌幸存者量身定制，以防止致命的脑 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.