Elucidating the role of gut, blood, and tumor microbiota in brain metastasis

项目摘要 脑转移瘤是一个重大的临床挑战，其发病率和死亡率不断上升 and mortality.了解脑转移瘤不同阶段的机制是至关重要的 发展早期诊断和预防方法以及有效的治疗策略， 改善这种疾病的结果。脑转移瘤的微环境通常是免疫抑制的， 提示免疫系统在脑转移过程中起关键作用。我们的团队和其他人 表明肠道和肿瘤微生物群在塑造免疫系统和肿瘤中起着重要作用。 在各种癌症中的免疫力。然而，微生物群的作用和微生物群驱动的免疫 脑转移的发生和进展的调节尚不清楚。越来越多的证据 表明肠道微生物群和大脑（即肠-脑轴）之间的动态相互作用， 最近的研究表明，原发性脑肿瘤中存在肿瘤内微生物标记， 微生物群在脑的肿瘤性和非肿瘤性疾病中的突出作用。符合这些 我们的初步研究表明，微生物读数可以在测序中检测到， 转移性脑肿瘤组织的数据集。根据这些初步调查结果和以前的研究， 从我们的团队和我们的合作者，我们发展了一个中心假设，即不同的肠道，血液和肿瘤， 微生物组特征可以调节脑中的免疫微环境以促进脑转移。 在具体目标1中，我们将确定与大脑相关的肠道，血液和肿瘤微生物组特征。 癌症患者的转移。我们将分析现有的全外显子组、全基因组和RNA测序 从脑转移患者收集的数据集，并将进行16 S rRNA基因扩增和宏基因组分析。 鸟枪测序分析前瞻性收集的粪便、血液和肿瘤中的微生物特征 脑转移患者的样本。我们将确定微生物特征与 有和没有脑转移的癌症患者的免疫概况。在具体目标2中，我们将进行 使用微生物组耗竭的临床前模型进行纵向研究，以确定微生物群在 脑转移瘤不同阶段的免疫调节和转移发展。与 由于微生物群易于检测和调节，因此拟议的研究具有 有可能揭示脑转移过程的新方面， 诊断、预防和治疗方法。

Project Summary Brain metastasis is a substantial clinical challenge associated with rising incidence and significant morbidity and mortality. Understanding the mechanisms underlying the different stages of brain metastasis is essential for the development of early diagnostic and preventive approaches and efficient therapeutic strategies to improve the outcome of this disease. The microenvironment in brain metastases is often immune-suppressed, suggesting a critical role for the immune system in the process of brain metastasis. Our group and others have demonstrated that gut and tumor microbiota have a major role in shaping the immune system and tumor immunity in a variety of cancer types. However, the role of microbiota and microbiota-driven immune modulation in the development and progression of brain metastasis is not clear. Growing evidence demonstrating a dynamic interaction between gut microbiota and the brain (i.e. gut-brain axis) along with recent studies showing the presence of intratumoral microbial signatures in primary brain tumors suggest a prominent role for the microbiota in neoplastic and non-neoplastic diseases of the brain. Consistent with these findings, our preliminary studies have demonstrated that microbial reads can be detected within sequencing datasets from metastatic brain tumor tissue. Building on these preliminary findings and the previous studies from our group and our collaborators, we developed the central hypothesis that distinct gut, blood, and tumor microbiome signatures can modulate the immune microenvironment in the brain to promote brain metastasis. In Specific Aim 1, we will identify the gut, blood, and tumor microbiome signatures associated with brain metastasis in cancer patients. We will analyze the existing whole exome, whole genome, and RNA sequencing datasets collected from brain metastasis patients and will conduct 16S rRNA gene amplicon and metagenomic shotgun sequencing to analyze the microbial signatures in prospectively collected fecal, blood, and tumor samples from brain metastasis patients. We will determine the association between microbial signatures and the immune profile in cancer patients with and without brain metastasis. In Specific Aim 2, we will conduct longitudinal studies using preclinical models of microbiome depletion to determine the role of microbiota in immune modulation and metastasis development during the different stages of brain metastasis. With microbiota being easily accessible for detection and targetable for modulation, the proposed studies have the potential to uncover novel aspects of the process of brain metastasis that can be leveraged to develop diagnostic, preventive, and therapeutic approaches for this disease.