Genes associated with fibroblast activation (ENC1, ST6GALNAC5, SEMA5A, TNFSF4) [36] typically showed a transcriptional increase in EV-depleted CRC organoid medium-treated fibroblasts in hypoxic conditions; however, we detected no additional fibroblast activating effect when EV-enriched medium was added in normoxia or hypoxia (Fig. S6e). Here, TNFSF4 is linked to colorectal carcinoma.