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.

Álvarez-Varela, A., Novellasdemunt, L., Barriga, F.M., Hernando-Momblona, X., Cañellas-Socias, A., Cano-Crespo, S., et al. (2022). Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. NATURE CANCER, 3(9), 1052-1070 [10.1038/s43018-022-00402-0].

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

Stassi, Giorgio;
2022-09-01

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.
set-2022
Álvarez-Varela, A., Novellasdemunt, L., Barriga, F.M., Hernando-Momblona, X., Cañellas-Socias, A., Cano-Crespo, S., et al. (2022). Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. NATURE CANCER, 3(9), 1052-1070 [10.1038/s43018-022-00402-0].
File in questo prodotto:
File Dimensione Formato  
Nat1052_compressed.pdf

Solo gestori archvio

Tipologia: Versione Editoriale
Dimensione 6.42 MB
Formato Adobe PDF
6.42 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/665843
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 58
  • ???jsp.display-item.citation.isi??? 54
social impact