title: ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a β-Cell-Induced Dedifferentiation.
abstract: Loss of pancreatic β-cell maturity occurs in diabetes and insulinomas. Although both physiological and pathological stresses are known to promote β-cell dedifferentiation, little is known about the molecules involved in this process. Here we demonstrate that activinB, a transforming growth factor β (TGF-β)-related ligand, is upregulated during tumorigenesis and drives the loss of insulin expression and β-cell maturity in a mouse insulinoma model. Our data further identify Pax4 as a previously unknown activinB target and potent contributor to the observed β-cell dedifferentiation. More importantly, using compound mutant mice, we found that deleting activinB expression abolishes tumor β-cell dedifferentiation and, surprisingly, increases survival without significantly affecting tumor growth. Hence, this work reveals an unexpected role for activinB in the loss of β-cell maturity, islet plasticity, and progression of insulinoma through its participation in β-cell dedifferentiation.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Doriane
authors.initials: D
authors.lastname: Ripoche
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Charbord
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Hennino
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Teinturier
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bonnavion
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Rami
authors.initials: R
authors.lastname: Jaafar
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Goehrig
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Cordier-Bussat
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Chang X
authors.initials: CX
authors.lastname: Zhang
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Andersson
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France philippe.bertolino@inserm.fr.
authors.forename: Philippe
authors.identifier: http://orcid.org/0000-0001-8064-8269
authors.initials: P
authors.lastname: Bertolino
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054337:Cell Dedifferentiation; D015972:Gene Expression Regulation, Neoplastic; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; C044147:activin B; D028341:Activins