Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy.

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-like phenotype and were unable to resist chemotherapy. Our findings reveal that adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identify a candidate cell of origin of relapse after treatment in CRC.