To recapitulate the CRC mutational landscape, Han and colleagues [163] generated mouse colonic organoids harbouring oncogenic Ptprk-Rspo3 fusions, KrasG12D or BrafV600E, and loss-of-function mutations in the tumour-suppressor genes p53 and Smad4. Transient exposure of these organoids to TGFβ, intended to select for Smad4-mutant lines, conferred resistance to PORCN inhibition, signifying that the emergent organoids had lost their dependence on Wnt signalling. The gene discussed is TP53; the disease is colorectal carcinoma.