Reciprocal Interactions Between the Gut Microbiome and Mammary Tissue Mast Cells Promote Metastatic Dissemination of HR+ Breast Tumors

• Published in: Cancer immunology research 2022-11, Vol.10 (11), p.1309-1325
• Main Authors: Feng, Tzu-Yu, Azar, Francesca N, Dreger, Sally A, Rosean, Claire Buchta, McGinty, Mitchell T, Putelo, Audrey M, Kolli, Sree H, Carey, Maureen A, Greenfield, Stephanie, Fowler, Wesley J, Robinson, Stephen D, Rutkowski, Melanie R
• Format: Article
• Language: English
• Subjects: Animals; Cell Transformation, Neoplastic; Dysbiosis; Gastrointestinal Microbiome; Mammary Neoplasms, Animal; Mast Cells - pathology; Neoplasm Recurrence, Local
• ISSN: 2326-6066; 2326-6074; 2326-6074
• DOI: 10.1158/2326-6066.CIR-21-1120

Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, before breast tumor initiation, enhances early dissemination of hormone receptor-positive (HR+) mammary tumor cells. Here, we sought to determine whether cellular changes occurring in normal mammary tissues, before tumor initiation and in response to dysbiosis, enhanced dissemination of HR+ tumors. Commensal dysbiosis increased both the frequency and profibrogenicity of mast cells in normal, non-tumor-bearing mammary tissues, a phenotypic change that persisted after tumor implantation. Pharmacological and adoptive transfer approaches demonstrated that profibrogenic mammary tissue mast cells from dysbiotic animals were sufficient to enhance dissemination of HR+ tumor cells. Using archival HR+ patient samples, we determined that enhanced collagen levels in tumor-adjacent mammary tissue positively correlated with mast cell abundance and HR+ breast cancer recurrence. Together, these data demonstrate that mast cells programmed by commensal dysbiosis activate mammary tissue fibroblasts and orchestrate early dissemination of HR+ breast tumors.