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Fibroblast heterogeneity drives metastatic spread in breast cancer through distinct mechanisms

ABSTRACT: The major cause of death among breast cancer patients is metastatic dissemination, suggesting that understanding the mechanisms driving this process remains an unmet medical need. Here, by concomitantly using 5 markers, we identify 4 Carcinoma-Associated Fibroblasts (CAF) subsets in primary tumors and corresponding metastatic lymph nodes (LN). Two CAF subsets, called CAF-S1 and CAF-S4, correlate with the proportion of cancer cells in invaded LN and exert distinct functions in tumor cell spread. CAF-S1 promote cancer cell migration and initiates an epithelial to mesenchymal transition through a CXCL12 / TGFb positive loop. For their part, the highly contractile CAF-S4 foster cancer cell motility and invasion in 3-dimensional matrix via Notch pathway activation. Finally, CAF-S1 and CAF-S4 accumulation in LN is a new prognostic factor at diagnostic, independent of breast cancer subtypes and LN status, strengthening the validity of our findings in human breast cancer pathophysiology.

PROVIDER: EGAS00001003238 | EGA |

REPOSITORIES: EGA

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