title: Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis.
abstract: OBJECTIVE
  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.
authors: Authors' Affiliations: INSERM U837 Team 4 "Molecular and Cellular Targeting of Cancers"; SIRIC ONCOLille; INSERM U837 Team 5 "Mucins, Epithelial Differentiation, and Carcinogenesis" Jean-Pierre Aubert Research Centre, Université Lille and CHU, Univ Nord de France; Unit of Biostatistics; Department of Digestive Surgery and Transplantation; Department of Medical Oncology, CHU, Univ Nord de France; IBL UMR-8161 CNRS, Université Lille Nord de France, Institut Pasteur, Lille; IRI USR 3078 CNRS, Villeneuve d'Ascq; INSERM U938, Molecular and Clinical Oncology, Hôpital Saint Antoine, Université Pierre et Marie Curie 6, Paris, France; and The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Yasmine
authors: Y
authors: Touil
authors: Wassila
authors: W
authors: Igoudjil
authors: Matthieu
authors: M
authors: Corvaisier
authors: Anne-Frédérique
authors: AF
authors: Dessein
authors: Jérôme
authors: J
authors: Vandomme
authors: Didier
authors: D
authors: Monté
authors: Laurence
authors: L
authors: Stechly
authors: Nicolas
authors: N
authors: Skrypek
authors: Carole
authors: C
authors: Langlois
authors: Georges
authors: G
authors: Grard
authors: Guillaume
authors: G
authors: Millet
authors: Emmanuelle
authors: E
authors: Leteurtre
authors: Patrick
authors: P
authors: Dumont
authors: Stéphanie
authors: S
authors: Truant
authors: François-René
authors: FR
authors: Pruvot
authors: Mohamed
authors: M
authors: Hebbar
authors: Fan
authors: F
authors: Fan
authors: Lee M
authors: LM
authors: Ellis
authors: Pierre
authors: P
authors: Formstecher
authors: Isabelle
authors: I
authors: Van Seuningen
authors: Christian
authors: C
authors: Gespach
authors: Renata
authors: R
authors: Polakowska
authors: Guillemette
authors: G
authors: Huet
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression; D019073:HT29 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D020360:Neoadjuvant Therapy; D061206:Neoplasm Micrometastasis / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016016:Proportional Hazards Models; D021381:Protein Transport; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D064447:Checkpoint Kinase 2; D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; C578634:CHEK2 protein, human; D005472:Fluorouracil