2. Academic Validation
  3. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy

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

  • Nat Cancer. 2022 Sep;3(9):1052-1070. doi: 10.1038/s43018-022-00402-0.
Adrián Álvarez-Varela 1 2,  Laura Novellasdemunt 1,  Francisco M Barriga 1 3,  Xavier Hernando-Momblona 1 2,  Adrià Cañellas-Socias 1 2,  Sara Cano-Crespo 1,  Marta Sevillano 1 2,  Carme Cortina 1 2,  Diana Stork 1,  Clara Morral 1,  Gemma Turon 1,  Felipe Slebe 1,  Laura Jiménez-Gracia 4,  Ginevra Caratù 4,  Peter Jung 5 6,  Giorgio Stassi 7,  Holger Heyn 4 8,  Daniele V F Tauriello 1 9,  Lidia Mateo 1,  Sabine Tejpar 10,  Elena Sancho 1 2,  Camille Stephan-Otto Attolini 1,  Eduard Batlle 11 12 13
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 2 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
  • 3 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 5 German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 6 German Cancer Consortium (DKTK), Partner site Munich, Institute of Pathology, Ludwig Maximilian University, Munich, Germany.
  • 7 Department of Surgical Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
  • 8 Universitat Pompeu Fabra, Barcelona, Spain.
  • 9 Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
  • 10 Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
  • 11 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. [email protected].
  • 12 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. [email protected].
  • 13 ICREA, Barcelona, Spain. [email protected].
PMID: 35773527 DOI: 10.1038/s43018-022-00402-0
Abstract

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.

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