Commensal dysbiosis distally reprograms mammary tissue mast cells to promote HR+ breast cancer metastasis 3436

Abstract Description Cancer is a leading cause of death among US women, with breast cancer accounting for 30% of new cases annually. While overall survival rates have improved, metastatic breast cancer cases remain a challenge. The hormone receptor-positive (HR+) Her2- subtype comprises the largest group of women with metastatic disease. However, there is a major gap in determining why certain patients are more susceptible to metastasis despite comparable initial diagnosis and treatments. This makes it imperative to identify modifiable host-intrinsic factors that promote metastasis. We have found that commensal dysbiosis, an inflammatory gut microbiome with low biodiversity, significantly increases HR+ tumor dissemination and metastasis. Importantly, mast cells were identified to play a central role in this process. Our data suggest that dysbiosis is causing phenotypic changes in mast cells that drive fibroblast activation and subsequent tumor dissemination. Tumor-associated fibroblasts are known to promote metastasis through immune suppression and fibrosis, but the factors driving their pro-metastatic behavior remain poorly understood. We hypothesize that gut dysbiosis reprograms mammary tissue mast cells to produce higher levels of pro-fibrogenic growth factors that promote differentiation of fibroblast subtypes that facilitate HR+ tumor dissemination. Through our findings, we aim to unravel the molecular mechanisms responsible for driving HR+ tumor metastasis. Funding Sources NIH/NCI 1R01CA253285 NIH/NCI 1R01CA262634 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)