SMAD4 and cancer: The accumulation of driver gene mutations promotes cancer development and malignant progression.2 Recent studies have shown that the transformation of human normal colonic stem cells can be achieved by the accumulation of APC, KRAS, SMAD4 and TP53-null mutations.4, 5 However, these transformed organoids failed to show a fully metastatic malignant behavior of human CRC.4, 31 In contrast, we herein show that triple mutations in ApcΔ716, KrasG12D and Trp53R270H showed liver metastasis after being injected into the spleen of NOG mice.