共生菌群失调介导乳腺组织肥大细胞与成纤维细胞的改变，从而促进HR+乳腺肿瘤的播散

We aim to uncover host-intrinsic factors influencing HR + breast cancer metastasis by focusing on interactions between mast cells and fibroblasts, two mammary tissue-associated cell types involved in the orchestration of metastatic breast cancer. Metastatic dissemination remains a significant barrier to reducing mortality associated with HR + Her2 - breast cancer. Dissemination occurs early and is driven by immune-mediated crosstalk between the tumor microenvironment and the adjacent tissue. We have demonstrated that commensal dysbiosis, an inflammatory gut microbiome with low biodiversity, promotes long-term cellular and molecular changes in normal (non-tumor-bearing) mammary tissues. When commensal dysbiosis is established in a mouse model before tumor initiation, dissemination of HR + breast tumor cells is significantly increased, whereas primary tumor growth remains unaffected. Gut microbiome changes have been associated with relapse and metastatic disease in women with breast cancer, highlighting the importance of defining how the gut microbiome regulates breast cancer through modulation of the mammary tissue environment. Our preliminary data suggest that dysbiosis activates a mast cell/fibroblast axis in the normal mammary tissue that enhances HR + tumor dissemination. We are using a combination of methods including but not limited to untargeted proteomics, spatial profiling, high-dimensional flow cytometry, scRNAseq, coupled with various in vivo and in vitro assays to define the contribution of this axis to early metastasis. Flow cytometry analysis and experiments using mast cell-deficient sash mice have demonstrated that dysbiosis increases the number of mammary tissue mast cells and causes changes in their phenotype. We have also observed that dysbiosis increases mammary tissue fibroblast activation in a mast cell-dependent mechanism. Supporting the role of mast cells in programming fibroblasts to promote breast tumor metastasis, spatial transcriptomic analysis has revealed a correlation between fibroblast activation and proximity to mast cells. Orthotopic transfer of fibroblasts from dysbiotic and non-dysbiotic mice has demonstrated that fibroblasts from the mammary tissues of dysbiotic mice are sufficient to increase early tumor dissemination. By uncovering mechanisms of mast cell-fibroblast crosstalk, our findings have the potential to inform the development of therapeutic and diagnostic strategies aimed at targeting tissue remodeling in patients at risk for metastatic disease. Ultimately, this work lays the foundation for repurposing clinically available drugs that target mast cell function or tissue fibrosis to prevent HR + breast cancer metastasis.