Title :

Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis

Author(s) :

Touil, Yasmine [Auteur]
Site de Recherche Intégrée en Cancérologie [SIRIC-ONCOLille]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Igoudjil, Wassila [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Corvaisier, Matthieu [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Dessein, Anne-Frédérique [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Vandomme, Jerome [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Monte, Didier [Auteur]
Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] [IRI]
Stechly, Laurence [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Skrypek, Nicolas [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Langlois, Carole [Auteur]
Unité de biostatistiques
Grard, Georges [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Millet, Guillaume [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Département de Chirurgie Digestive B et Transplantation [Hôpital Saint-Eloi - CHU Montpellier]
Leteurtre, Emmanuelle [Auteur]

Dumont, Patrick [Auteur]
Institut de biologie de Lille - IBL [IBLI]
Truant, Stéphanie [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Département de Chirurgie Digestive B et Transplantation [Hôpital Saint-Eloi - CHU Montpellier]
Pruvot, Francois-Rene [Auteur]
Département de Chirurgie Digestive B et Transplantation [Hôpital Saint-Eloi - CHU Montpellier]
Hebbar, Mohamed [Auteur]

Service d'oncologie médicale
Fan, Fan [Auteur]
The University of Texas M.D. Anderson Cancer Center [Houston]
Ellis, Lee M. [Auteur]
The University of Texas M.D. Anderson Cancer Center [Houston]
Formstecher, Pierre [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
VAN SEUNINGEN, ISABELLE [Auteur]

Gespach, Christian [Auteur]

Polakowska, Renata [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Huet, Guillemette [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]

Journal title :

Clinical cancer research

Abbreviated title :

Clin. Cancer Res.

Volume number :

20

Pages :

837-846

Publication date :

2014-02-15

ISSN :

1078-0432

English keyword(s) :

Gene Expression
Cell Proliferation
Humans
Kaplan-Meier Estimate
Proportional Hazards Models
Drug Resistance, Neoplasm
Neoplastic Stem Cells
Liver Neoplasms
Biomarkers, Tumor
Nuclear Proteins
Protein Transport
HT29 Cells
Disease-Free Survival
Cell Cycle Checkpoints
Neoplasm Micrometastasis
Proto-Oncogene Proteins c-yes
Checkpoint Kinase 2
Antimetabolites, Antineoplastic
Neoadjuvant Therapy
Transcription Factors
Chemotherapy, Adjuvant
Cell Nucleus
Colonic Neoplasms
Fluorouracil

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

PURPOSE: Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired ...
Show more >PURPOSE: Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. RESULTS: We show that a clonal 5F31 cell population, resistant to 1 μmol/L 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, YES1 and YAP transcript levels were higher in liver metastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively). CONCLUSIONS: We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer.Show less >

Language :

Anglais

Audience :

Non spécifiée

Administrative institution(s) :

CHU Lille
CNRS
Inserm
Université de Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Research team(s) :

Biologie structurale et intégrative

Submission date :

2020-02-12T15:11:29Z
2021-03-11T13:16:17Z
2021-06-15T12:12:51Z