Resumen de Identification of colorectal cancer cells that mediate relapse after chemotherapy by marker gene mex3a
Colorectal Cancer (CRC) patient-derived organoids (PDOs) predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Whereas PDOs expand from highly proliferative LGR5+ tumor cells, we discovered that lack of optimal growth conditions specifies a latent LGR5+ cell state. This cell population expressed the gene MEX3A, were 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 of that of YAP+ fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated towards 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.
