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Cross-talk between Cancer-Associated Fibroblasts and Triple Negative Breast Cancer (TNBC) cells in heterotypic clusters

ABSTRACT: Circulating Cancer-Associated Fibroblasts (cCAFs) have been discovered in circulating tumor cell clusters from all stages of disease progression in breast cancer patients. As the most abundant non-cancerous cell type in the tumor microenvironment (TME), CAFs impart many of the tumor promoting functions defined by the hallmarks of cancer such as: proliferation, invasion, migration, metastasis, stemness, immunosuppression, altered cancer cell metabolism, and drug resistance. Human primary CAF cell lines can form co-clusters in vitro with human breast cancer cells when grown in ultra-low attachment conditions. We have previously used these co-clusters to show that they promote metastasis in the mouse tail vein model. In this study, we seek to understand the cross-talk that occurs between CAFs and TNBC cells when they are present in heterotypic co-clusters compared to TNBC monoclusters or CAF monoclusters. We created samples of mono-clusters and co-clusters grown in 3D conditions for 48 hrs, then disrupted the clusters into a single cell suspension, and subsequently processed them for Single-cell RNA sequencing. Comparisons of breast cancer cells grown as mono-clusters versus co-clusters revealed differentially expressed genes (DEGs) that are up and down regulated in the presence of CAFs. Integration Pathway Analysis and Gene Ontology analysis revealed that CAFs increase expression of several components of the fibrinolysis pathway in breast cancer cells, such as uPA/PLAU and SERPINE1. Upstream regulators identified included TGFbeta. We also looked at DEGs in CAFs when in co-clusters versus mono-clusters and found that when in co-clusters, CAFs become even more CAF-like with the upregulation of genes such as collagens, integrins, and FN1. This study provided us with candidates to study in the process of CAF-mediated breast cancer cell extravasation, such as uPA/PLAU. Pathways identified support our conclusions that circulating CAFs are important players in the metastatic process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300584 | GEO | 2025/06/25

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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Cross-talk between Cancer-Associated Fibroblasts and Triple Negative Breast Cancer (TNBC) cells in heterotypic clusters

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