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
  • 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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