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

Autor:	Álvarez-Varela A; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain., Novellasdemunt L; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Barriga FM; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Hernando-Momblona X; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain., Cañellas-Socias A; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain., Cano-Crespo S; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Sevillano M; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain., Cortina C; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain., Stork D; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Morral C; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Turon G; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Slebe F; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Jiménez-Gracia L; CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain., Caratù G; CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain., Jung P; German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner site Munich, Institute of Pathology, Ludwig Maximilian University, Munich, Germany., Stassi G; Department of Surgical Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy., Heyn H; CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.; Universitat Pompeu Fabra, Barcelona, Spain., Tauriello DVF; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Mateo L; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Tejpar S; Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium., Sancho E; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain., Stephan-Otto Attolini C; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain., Batlle E; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. eduard.batlle@irbbarcelona.org.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. eduard.batlle@irbbarcelona.org.; ICREA, Barcelona, Spain. eduard.batlle@irbbarcelona.org.
Jazyk:	angličtina
Zdroj:	Nature cancer [Nat Cancer] 2022 Sep; Vol. 3 (9), pp. 1052-1070. Date of Electronic Publication: 2022 Jun 30.
DOI:	10.1038/s43018-022-00402-0
Abstrakt:	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. (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze:	MEDLINE
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