In accordance with the previous studies that showed the TGFβ/Smad signaling pathway as a key regulator of epithelial-mesenchymal transition (EMT)21, we found that the CM from FHC cells educated by EV-mtDNA induced a TGFβ1-dependent EMT phenotype in tumor cells, characterized by increased levels of phosphorylated Smad2/3, Vimentin, and Snai1 and decreased level of E-cadherin (Fig. 6f and Supplementary Fig. 12h). Here, SMAD2 is linked to neoplasm.