title: Melanoma dormancy in a mouse model is linked to GILZ/FOXO3A-dependent quiescence of disseminated stem-like cells.
abstract: Metastatic cancer relapses following the reactivation of dormant, disseminated tumour cells; however, the cells and factors involved in this reactivation are just beginning to be identified. Using an immunotherapy-based syngeneic model of melanoma dormancy and GFP-labelled dormant cell-derived cell lines, we determined that vaccination against melanoma prevented tumour growth but did not prevent tumour cell dissemination or eliminate all tumour cells. The persistent disseminated melanoma tumour cells were quiescent and asymptomatic for one year. The quiescence/activation of these cells in vitro and the dormancy of melanoma in vivo appeared to be regulated by glucocorticoid-induced leucine zipper (GILZ)-mediated immunosuppression. GILZ expression was low in dormant cell-derived cultures, and re-expression of GILZ inactivated FOXO3A and its downstream target, p21CIP1. The ability of dormancy-competent cells to re-enter the cell cycle increased after a second round of cellular dormancy in vivo in association with shortened tumour dormancy period and faster and more aggressive melanoma relapse. Our data indicate that future cancer treatments should be adjusted according to the stage of disease progression.
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.|Faculté de Médecine, Université de Lille, 59000 Lille, France.|SIRIC ONCOLille, Lille, France.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Touil
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.|Faculté de Médecine, Université de Lille, 59000 Lille, France.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Segard
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Ostyn
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.
authors.forename: Severine
authors.initials: S
authors.lastname: Begard
authors.affiliation: Institut A. Bonniot, Ontogenèse et Oncogenèse Moléculaires, UMR EFS-UJF-INSERM 823, Immunobiology and Immunotherapy of Cancers, Grenoble, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Aspord
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.
authors.forename: Raja
authors.initials: R
authors.lastname: El Machhour
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.|Faculté de Médecine, Université de Lille, 59000 Lille, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Masselot
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.|Faculté de Chirurgie Dentaire, Université de Lille, 59000 Lille, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Vandomme
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.
authors.forename: Pilar
authors.initials: P
authors.lastname: Flamenco
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Idziorek
authors.affiliation: Faculté de Médecine, Université de Lille, 59000 Lille, France.|Plateforme de Génomique Fonctionnelle, IRCL, 59045 Lille, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Figeac
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.|Faculté de Médecine, Université de Lille, 59000 Lille, France.|Cancéropôle Nord-Ouest, 6 rue du Professeur Laguesse, 59045 Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Formstecher
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.|Faculté de Médecine, Université de Lille, 59000 Lille, France.|Service des Maladies du Sang, CHRU de Lille, 59037 Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.affiliation: Inserm UMR-S1172 Centre de Recherche Jean Pierre Aubert (JPArc), Institut pour la Recherche sur le Cancer de Lille (IRCL), 1 Place de Verdun, 59045 Lille, France.
authors.forename: Renata
authors.initials: R
authors.lastname: Polakowska
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3 / Q000235:genetics*; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016192:Resting Phase, Cell Cycle / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C404226:TSC22D3 protein, human; D014157:Transcription Factors