Using mouse models of murine and human colorectal cancer, Fumagalli and colleagues (49) showed that circulating colorectal cancer cells were primarily Lgr5– and that the Lgr5– cells were responsible for distant metastases; however, via plasticity, Lgr5– cells become Lgr5+ CSCs in a niche-independent manner, restoring the hierarchy of the original tumor in metastatic lesions. The gene discussed is LGR5; the disease is colorectal cancer.