SMAD4 and neoplasm: Similar observations were made by Melo et al, who generated mouse-derived intestinal tumour organoids mimicking the sequential acquisition of mutations that occur during human CRC progression (APC, Kras, Trp53, Smad4).69 Using this model, limiting-dilution transplants of FACS-sorted tumour cells showed that tumour-initiating capacity was enriched in the LGR5+ tumour-cell fractions; however, LGR5− cells could also regenerate tumours that subsequently contained LGR5+ sub-populations.