Deciphering the Role of Intestinal Crypt Cell Populations in Resistance to Chemotherapy

Abstract Intestinal crypts are composed of heterogeneous and highly plastic cell populations. Lgr5high-stem cells (SC) responsible for homeostatic renewal, but other can revert to an SC-like phenotype maintain epithelial integrity. Despite their distinct roles in orchestrating homeostasis, both populations have been designated as the putative “cell-of-origin” colorectal cancer. However, respective involvement emergence drug-resistant cancer SCs (CSC), tumor relapse associated with poor outcome cancer, remains elusive. In this context, intestinal SC/progenitor-marker Musashi1 (MSI1) is interesting it plays important functions homeostasis frequently overexpressed human Therefore, our aims were: (i) study impact chemotherapy on Lgr5-expressing MSI1-expressing populations, (ii) explore effect increased MSI1 levels response treatment, (iii) evaluate relevance Engineered mouse models treated therapeutic agent 5-fluorouracil showed that upon levels, Lgr5high remain sensitive while Lgr5low progenitors reprogram a phenotype. This resulted expansion subpopulation improved resistance DNA damage detoxification, typical properties dormant-CSCs reactivate after chemotherapy. Analysis patients revealed correlation between grading, CSC phenotype, chemoresistance. Altogether, these results shed new light biology plasticity normal crypt also open perspectives target improve outcome. Significance: unveils paradoxical MSI1, underlining its importance facilitating regeneration injury unraveling function stem cells.