Collectively, our in vitro, in vivo, and ex vivo results demonstrated a critical role for WNT3 induction in mediating CSC activation and recurrence in 5-FU-treated CRCs with wild-type p53. Despite the initial tumor de-bulking, the 5-FU-treated tumors regrew due to CSC activation via p53-mediated transcriptional WNT3 induction. Here, WNT3 is linked to neoplasm.