Cholangiocarcinoma (CCA) is a highly desmoplastic tumor characterized by a complex and dynamic tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) coexist and crosstalk with cancer cells and other stromal cell types. In our recent publications, we have identified hepatic stellate cells (HSC) as the main cell source of CAFs in the liver, and HSC-derived CAFs as dominant population interacting with tumor cells using genetic tracing, single-cell RNA-sequencing and ligand-receptor analyses. This discovery allowed us to define the overall tumor promoting role of CAFs in mice models of CCA. However, single-cell RNA-sequencing and functional studies, revealed CAF heterogeneity, with the presence of several CAF subtypes, some promoting- and some-restricting tumor growth. During this talk, we will discuss the different shades of CAFs in cholangiocarcinogenesis and their potential in combined therapies aimed at targeting not only the tumor cells, but also the complexity of its TME.<\/p>\n
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