Although loss of SMAD4 isa key event in CRC progression, the resulting changes in biologicalprocesses in advanced disease and metastasis are not fully understood.Here, we applied a multiomics approach to a CRC organoid model thatfaithfully reflects the metastasis-supporting effects of SMAD4 inactivation.We show that loss of SMAD4 results in decreased differentiation andactivation of pro-migratory and cell proliferation processes, whichis accompanied by the disruption of several key oncogenic pathways,including the TGFβ, WNT, and VEGF pathways. This evidence concerns the gene VEGFA and colorectal carcinoma.