Dissecting the Stroma-Tumor cross talk in Breast Cancer: the impact of Cancer Associated Fibroblasts on Drug Resistance

Breast cancer (BC) remains a significant public health concern worldwide, with diverse subtypes and multiple mechanisms contributing to its progression and resistance to treatments. One crucial aspect influencing breast cancer behavior is the tumor microenvironment (TME), a complex niche comprising various non-cancerous cell types, extracellular matrix components, and signaling molecules. Among the key players within the TME are cancer-associated fibroblasts (CAFs), which become activated in response to tumor-derived signals. Emerging evidence suggests that CAFs play a pivotal role in promoting breast cancer progression and therapy resistance. For this reason, understanding the mechanisms regulating the cross talk between breast cancer cells and CAFs within the TME is critical for developing effective therapeutic strategies. Here, we characterized a number of human cancer-associated fibroblast cell lines in terms of gene expression, protein secretion, and ability to promote human breast cancer cell proliferation. We could demonstrate how CAFs are able to induce strong upregulation of BC putative genes involved in the cancer-stroma cross talk, like ceruloplasmin and CXCL12. Moreover, we set up the conditions for the first phase of a broader project, which aims at identifying the molecular players driving resistance to therapy. We carried out a drug resistance screening on multiple BC lines to identify combinations of BC-CAF-drugs displaying a CAF-driven decrease in therapy sensitivity. Finding genes responsible for this phenotype and subsequently new compounds able to effectively disrupt their activity may represent a turning point in overcoming drug resistance in breast cancer.