TY - JOUR
T1 - Deciphering the role of intestinal crypt cell populations in resistance to chemotherapy
AU - Frau, Carla
AU - Jamard, Catherine
AU - Delpouve, Gaspard
AU - Guardia, Gabriela D.A.
AU - Machon, Christelle
AU - Pilati, Camilla
AU - Le Neve, Clementine
AU - Laurent-Puig, Pierre
AU - Guitton, Jer ôme
AU - Galante, Pedro A.F.
AU - Penalva, Luiz O.
AU - Freund, Jean Noel
AU - De La Fouchardiere, Christelle
AU - Plateroti, Michelina
N1 - Funding Information:
The authors are grateful to Manon Prativiel for her assistance with animal handling and care within the AniCan animal facility (CRCL). The authors also acknowledge the imaging, cytometry, and Anipath Recherche small animal histology platforms (CRCL, CLB). They are indebted to the ex vivo platform (CLB) for help in fresh sample collection and to the Surgical and Anathomopathology Departments of the CLB. They also thank Maria Ouzounova and Alain Puisieux for the gift of RSPO-expressing cells, Maria Virginia Giolito, Sebastien Ibanez, Arnaud Vigneron, and Jean Jacques Diaz for their insightful suggestions. The authors are grateful to the AniRA lentivectors production facility from the CELPHEDIA Infrastructure and SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL), especially Caroline Costa, Gisele Froment, and Didier Negre. They are also indebted to Brigitte Manship for critical reading of the manuscript. The work was supported by the the Inca (PLBIO14-292), by the FRM (Equipes FRM 2018, DEQ20181039598), and by the Inca (PLBIO19-289). C. Frau received support from the Fondation ARC and from the Centre Leon Berard and G.D. Guardia received support from FAPESP (2017/19541-2).
Funding Information:
The authors are grateful to Manon Prativiel for her assistance with animal handling and care within the AniCan animal facility (CRCL). The authors also acknowledge the imaging, cytometry, and Anipath Recherche small animal histology platforms (CRCL, CLB). They are indebted to the ex vivo platform (CLB) for help in fresh sample collection and to the Surgical and Anathomopathology Departments of the CLB. They also thank Maria Ouzounova and Alain Puisieux for the gift of RSPO-expressing cells, Maria Virginia Giolito, Sebastien Ibanez, Arnaud Vigneron, and Jean Jacques Diaz for their insightful suggestions. The authors are grateful to the AniRA lentivectors production facility from the CELPHEDIA Infrastructure and SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL), especially Caroline Costa, Gisèle Froment, and Didier Nègre. They are also indebted to Brigitte Manship for critical reading of the manuscript. The work was supported by the the Inca (PLBIO14-292), by the FRM (Equipes FRM 2018, DEQ20181039598), and by the Inca (PLBIO19-289). C. Frau received support from the Fondation ARC and from the Centre Leon Berard and G.D. Guardia received support from FAPESP (2017/19541-2).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/5
Y1 - 2021/5
N2 - Intestinal crypts are composed of heterogeneous and highly plastic cell populations. Lgr5high-stem cells (SC) are responsible for homeostatic renewal, but other cells can revert to an SC-like phenotype to maintain epithelial integrity. Despite their distinct roles in orchestrating homeostasis, both populations have been designated as the putative “cell-of-origin” of colorectal cancer. However, their respective involvement in the emergence of drug-resistant cancer SCs (CSC), responsible for tumor relapse and associated with poor outcome of colorectal cancer, remains elusive. In this context, the intestinal SC/progenitor-marker Musashi1 (MSI1) is interesting as it plays important functions in intestinal homeostasis and is frequently overexpressed in human colorectal cancer. Therefore, our aims were: (i) to study the impact of chemotherapy on Lgr5-expressing and MSI1-expressing cell populations, (ii) to explore the effect of increased MSI1 levels in response to treatment, and (iii) to evaluate the relevance in human colorectal cancer. Engineered mouse models treated with the therapeutic agent 5-fluorouracil showed that upon increased MSI1 levels, Lgr5high SCs remain sensitive while Lgr5low progenitors reprogram to a drug-resistant phenotype. This resulted in the expansion of an MSI1-expressing cell subpopulation with improved resistance to DNA damage and increased detoxification, typical properties of dormant-CSCs that can reactivate after chemotherapy. Analysis in patients with colorectal cancer revealed a correlation between MSI1 levels and tumor grading, CSC phenotype, and chemoresistance. Altogether, these results shed new light on the biology and plasticity of normal crypt and cancer cell populations and also open new perspectives to target MSI1 to improve chemotherapy outcome. Significance: This study unveils paradoxical roles for MSI1, underlining its importance in facilitating intestinal regeneration upon injury but also unraveling its new function in drug-resistant colorectal cancer stem cells.
AB - Intestinal crypts are composed of heterogeneous and highly plastic cell populations. Lgr5high-stem cells (SC) are responsible for homeostatic renewal, but other cells can revert to an SC-like phenotype to maintain epithelial integrity. Despite their distinct roles in orchestrating homeostasis, both populations have been designated as the putative “cell-of-origin” of colorectal cancer. However, their respective involvement in the emergence of drug-resistant cancer SCs (CSC), responsible for tumor relapse and associated with poor outcome of colorectal cancer, remains elusive. In this context, the intestinal SC/progenitor-marker Musashi1 (MSI1) is interesting as it plays important functions in intestinal homeostasis and is frequently overexpressed in human colorectal cancer. Therefore, our aims were: (i) to study the impact of chemotherapy on Lgr5-expressing and MSI1-expressing cell populations, (ii) to explore the effect of increased MSI1 levels in response to treatment, and (iii) to evaluate the relevance in human colorectal cancer. Engineered mouse models treated with the therapeutic agent 5-fluorouracil showed that upon increased MSI1 levels, Lgr5high SCs remain sensitive while Lgr5low progenitors reprogram to a drug-resistant phenotype. This resulted in the expansion of an MSI1-expressing cell subpopulation with improved resistance to DNA damage and increased detoxification, typical properties of dormant-CSCs that can reactivate after chemotherapy. Analysis in patients with colorectal cancer revealed a correlation between MSI1 levels and tumor grading, CSC phenotype, and chemoresistance. Altogether, these results shed new light on the biology and plasticity of normal crypt and cancer cell populations and also open new perspectives to target MSI1 to improve chemotherapy outcome. Significance: This study unveils paradoxical roles for MSI1, underlining its importance in facilitating intestinal regeneration upon injury but also unraveling its new function in drug-resistant colorectal cancer stem cells.
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UR - http://www.scopus.com/inward/citedby.url?scp=85106175272&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-2450
DO - 10.1158/0008-5472.CAN-20-2450
M3 - Article
C2 - 33741693
AN - SCOPUS:85106175272
SN - 0008-5472
VL - 81
SP - 2730
EP - 2744
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -