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Alvarez-Varela, Adrian; Novellasdemunt, Laura; Barriga, Francisco M.; Hernando-Momblona, Xavier; Canellas-Socias, Adria; Cano-Crespo, Sara; Sevillano, Marta; Cortina, Carme; Stork, Diana; Morral, Clara; Turon, Gemma; Slebe, Felipe; Jimenez-Gracia, Laura; Caratu, Ginevra; Jung, Peter; Stassi, Giorgio; Heyn, Holger; Tauriello, Daniele V. F.; Mateo, Lidia; Tejpar, Sabine; Sancho, Elena; Stephan-Otto Attolini, Camille and Batlle, Eduard (2022): Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. In: Nature Cancer, Vol. 3, No. 9: pp. 1052-1070

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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-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. Batlle and colleagues report that after chemotherapy, Mex3a(+) colorectal cancer cells represent drug-tolerant persister cells that lead to recurrence by downregulating the WNT-Lgr5(+) stem cell program and adopting a transient regenerative state.

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