For these experiments, we initially selected a PDO derived from a stage IV CRC that displayed a prototypical combination of genetic alterations in major driver pathways including activation of the WNT pathway by APC loss of function, activation of EGFR signaling by KRAS G13D mutations, and loss of TGF‐beta‐mediated tumor suppression by inactivating mutations in SMAD4 (PDO#7 in Appendix Table S1). This evidence concerns the gene SMAD4 and colorectal carcinoma.