Distal inflammatory priming of normal mammary tissue by the gut microbiome drives breast tumor metastasis via metabolic dysregulation

Abstract

Hormone receptor-positive (HR +), HER2 −is the most prevalent metastatic breast cancer subtype, constituting 73.1% of the metastatic disease population in the US. Despite targeted therapies that have increased long-term survival, many patients develop and eventually succumb to metastatic disease. Tumor dissemination occurs early during disease progression and is driven by cellular and molecular changes in the tissue. Though host-intrinsic factors that preferentially predispose certain individuals to metastatic disease are poorly defined, gut microbial health has become increasingly recognized as a determinant of the metastatic potential of breast tumors. We demonstrated that commensal dysbiosis, an inflammatory gut microbiome with low biodiversity, drives HR +tumor metastasis. Our work identified that a dysbiosis-induced CCL2/mast cell axis in normal (non-tumor-bearing) mammary tissues acts as a master regulator of early metastasis. Our present goal is to define how gut dysbiosis triggers tissue inflammation. We present evidence that dysbiosis-induced metabolic dysregulation increases early dissemination of HR +tumors by initiating cellular and molecular changes in normal mammary tissue. Dysbiosis results in systemic insulin-glucose dynamics that resemble an insulin resistant phenotype. Additionally, we find that acylcarnitine species, byproducts of incomplete fatty acid β-oxidation which we hypothesize promote local tissue inflammation, accumulate in normal mammary tissues of dysbiotic mice. Altogether, we propose that commensal dysbiosis triggers a systemic metabolic shift that enhances the metastatic potential of HR +tumors by shaping the immune landscape of the pre-cancerous mammary tissues. Supported by grants from NIH (1RO1 CA253285, 2T32AI007496-26A1)