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

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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.