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

项目摘要 脑转移是一个巨大的临床挑战，与发病率上升和显著的发病率有关。 和死亡率。了解脑转移不同阶段的潜在机制是至关重要的。 制定早期诊断和预防方法以及有效的治疗策略 改善这种疾病的结局。脑转移瘤的微环境通常是免疫抑制的， 这表明免疫系统在脑转移过程中起着关键作用。我们的团队和其他人 证明肠道和肿瘤微生物区系在免疫系统和肿瘤的形成中起着重要作用 在多种癌症类型中具有免疫力。然而，微生物区系的作用和微生物区系驱动的免疫 脑转移瘤的发生发展过程中的调控机制尚不清楚。越来越多的证据 演示肠道微生物区系与大脑(即肠道-脑轴)之间的动态相互作用以及 最近的研究表明，在原发性脑肿瘤中存在肿瘤内的微生物特征，这表明 微生物区系在脑部肿瘤和非肿瘤性疾病中的突出作用。与这些一致 我们的初步研究表明，微生物读数可以在测序中检测到 来自转移性脑瘤组织的数据集。以这些初步发现和以前的研究为基础 从我们的团队和我们的合作者那里，我们提出了一个中心假设，即不同的肠道、血液和肿瘤 微生物组特征可以调节大脑中的免疫微环境，促进脑转移。 在特定目标1中，我们将识别与大脑相关的肠道、血液和肿瘤微生物组特征。 癌症患者的转移。我们将分析现有的整个外显子组、全基因组和rna序列。 收集自脑转移患者的数据集，并将进行16S rRNA基因扩增和元基因组学 用鸟枪测序法分析预期采集的粪便、血液和肿瘤中的微生物特征 来自脑转移患者的样本。我们将确定微生物签名和 有脑转移和无脑转移癌症患者的免疫状态。在具体目标2中，我们将进行 使用临床前微生物组耗竭模型进行的纵向研究，以确定微生物区系在 脑转移瘤不同阶段的免疫调节和转移发展。使用 由于微生物区系易于检测，并可作为调节的目标，拟议的研究具有 有可能发现脑转移过程中可用于开发的新方面 这种疾病的诊断、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.