We have previously found that SW480 CRC cells, which have mutant SMAD4, are also sensitive to galunisertib in the VMT but not in spheroid cultures, and that SW480 reprogram the fibroblasts within the VMT toward a CAF phenotype with activated TGF-β signaling.15 A similar phenomenon has been described in clinical CRC disease,33 warranting further investigation into the mechanism of action for galunisertib to better understand this pathology. This evidence concerns the gene SMAD4 and colorectal carcinoma.