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Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5⁺ tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5⁺ cell state. This cell population expressed the gene MEX3A, is chemoresistant and regenerated the organoid culture after treatment. In CRC mouse models, Mex3a⁺ cells contributed marginally to metastatic outgrowth; however, after chemotherapy, Mex3a⁺ cells produced large cell clones that regenerated the disease. Lineage-tracing analysis showed that persister Mex3a⁺ cells downregulate the WNT/stem cell gene program immediately after chemotherapy and adopt a transient state reminiscent to that of YAP⁺ fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated toward a goblet cell …