SMAD4 and neoplasm: Numerous studies, using genetically-engineered-mouse models (GEMMs), have shown loss of Smad4 or Tgfbr1/2, in concert with other key mutational drivers of CRC (loss of Apc and/or expression of oncogenic KRAS), accelerates intestinal tumourigenesis and promotes tumour progression, positioning TGFβ signalling as a fundamental tumour suppressor in CRC12–14.