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

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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.