Single-cell genomic analysis of triple-negative breast cancer fibroblasts uncovers evolutionarily conserved features and potential therapeutic targets

Abstract

SummaryTo explore cancer associated fibroblasts (CAFs) in triple-negative breast cancers (TNBC), we performed scRNA-seq analysis of fibroblasts from murine and human TNBCs. We observed three distinct CAF subtypes in mouse TNBC: two that are intermingled and adjacent to tumor cells, and one that is more distal. We present evidence that progression of CAFs from normal resident fibroblasts/pericytes involves upregulation of their Pdgf and Tgfb receptors along with reciprocal ligand upregulation in other cells within the tumor microenvironment. Additionally, extracellular matrix, glycolytic, and mitochondrial respiratory genes are strongly upregulated in all CAFs. Activation of extracellular matrix genes specifically in CAFs and not in normal fibroblasts provides numerous targets for CAF-based therapeutics, many of which are conserved in CAFs from human TNBC. In contrast, the subtype structure of CAFs was less conserved, which along with their transcriptional heterogeneity suggests that molecular targeting of CAFs is more practical than targeting CAF subtypes.