Paracrine communication between tumor and surrounding stroma arbitrates the malignant behavior of cancer progression [1]. Fibroblasts, which are the main cell type within the stroma and are called cancer-associated fibroblasts (CAFs), orchestrate the crosstalk with cancer cells [2, 3] and express several markers associated with prognosis [4]. There is increasing evidence that a stromaspecific signature could be used for risk assessment in colon cancer (CC). According to the Consensus Molecular Subtype classification (CMS) in CC, the mesenchymal or CMS4 group is characterized by stromal invasion, extracellular matrix remodeling and TGF-β signaling activation. It is associated with the worst prognosis rates [5, 6]. Genes correlating with the mesenchymal subtype are mostly expressed by CAFs and other stromal cells, rather than by tumor cells [7]. Accordingly, our group defined a gene expression profile associated with CAFs with high pro-migratory effects on colon tumor cells, which was associated with patients’ poor prognosis. These were mostly advanced-stage patients [8]. The crosstalk between tumor and stromal cells is conducted in part by exosomes that are involved in many tumorogenic processes. ncRNAs contained in exosomes secreted by colon CAFs enhance proliferation and stemness properties of tumoral cells and are involved in chemoresistance [9]. Recently, our group demonstrated that there was a difference in how CAFs and normal colon mucosa fibroblasts (NFs) distributed ncRNA into the exosomal cargo. There was the same difference in distribution for their potential ncRNA target genes in recipient cells [10]. Our research into CAF profiles and targets of CAF-derived exosome cargo in recipient cells found novel CAF-derived signatures with prognostic value in colon cancer patients. This showed the importance of CAFs and their derived exosomes in tumor progression (Fig. 1).