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Comparative single-cell genomics uncovers evolutionarily conserved features and therapeutic targets in triple-negative breast cancer fibroblasts

ABSTRACT: We performed scRNA-seq analysis of fibroblasts from murine and human TNBCs. We observed three CAF subtypes in mouse TNBC: two transcriptionally distinct CAFs that were found intermingled and adjacent to tumor cells, and distal CAFs that were located further away from tumor cells. All three CAFs appear to evolve from normal resident fibroblasts/pericytes by activation of Pdgf and Tgfb receptors in fibroblasts in parallel with reciprocal upregulation of ligands in tumor cells and other tumor microenvironment cells. Additionally, extracellular matrix, glycolytic and mitochondrial respiratory genes were strongly upregulated in all three CAFs. Murine pancreatic CAFs displayed matching subtypes. Human TNBCs displayed three analogous CAF subtypes, although only a subset of marker genes are conserved. Finally, the upregulation of specific extracellular matrix genes in different CAF subtypes provides a basis for developing selective CAF-targeted therapeutics.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE199515 | GEO | 2022/09/01

REPOSITORIES: GEO

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Project description:Breast cancer is a heterogeneous disease for which prognosis and treatment strategies are largely governed by the receptor status (estrogen, progesterone and Her2-neu) of the tumor cells. Gene expression profiling of whole breast tumors further stratifies breast cancer into several molecular subtypes which also co-segregate with the receptor status of the tumor cells. We postulated that cancer associated fibroblasts (CAFs) within the tumor stroma may exhibit subtype specific gene expression profiles and thus contribute to the biology of the disease in a subtype specific manner. Several studies have reported gene expression profile differences between CAFs and normal breast fibroblasts but in none of these studies were the results stratified based on tumor subtypes. To address whether gene expression in breast cancer associated fibroblasts varies between breast cancer subtypes, we compared the gene expression profiles of early passage primary CAFs isolated from twenty human breast cancer samples representing three main subtypes; seven ER+, seven triple negative (TNBC) and six Her2+. We observed significant expression differences between CAFs derived from Her2+ breast cancer and CAFs from TNBC and ER+ cancers, particularly in pathways associated with cytoskeleton and integrin signaling. In the case of Her2+ breast cancer, the signaling pathways found to be selectively up regulated in CAFs may contribute to the more invasive properties and unfavorable prognosis of Her2+ breast cancer. These data demonstrate that in addition to the distinct molecular profiles that characterize the neoplastic cells, CAF gene expression is also differentially regulated in distinct subtypes of breast cancer. We isolated CAFs from twenty primary breast cancer samples representing three main subtypes (ER+ (n=7), TNBC (n=7), Her2+ (n=6)) and performed gene expression profile analyses on RNA isolated from these early passage CAFs. Those samples were done in two batches with 4 samples repeated in both batches. One TNBC sample was found to be an outlier and not used in the analysis.

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Comparative single-cell genomics uncovers evolutionarily conserved features and therapeutic targets in triple-negative breast cancer fibroblasts

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