Indeed, using intravital multiphoton microscopy to observe spontaneous metastatic progression from orthotopically implanted, genome-edited CRC organoids [301], van Rheenen and colleagues made the striking observation that the majority of circulating tumour cells lacks Lgr5. In vitro, Lgr5− cells were intrinsically competent to form organoids and spawn functional Lgr5+ progeny, independently of niche signals, although the emergence of Lgr5+ cells was increased in the presence of HGF and FGF [302]. This evidence concerns the gene LGR5 and colorectal carcinoma.