title: Deciphering the molecular basis of invasiveness in Sdhb-deficient cells.
abstract: Metastatic pheochromocytomas and paragangliomas (PPGL) are malignant neuroendocrine tumors frequently associated with germline mutations in the SDHB gene. SDHB-mutated PPGL display a hypermethylator phenotype associated with hallmarks of epithelial-to-mesenchymal transition (EMT). In the present study, we report the characterization of a unique model of Sdhb knockout in mouse chromaffin cells. Sdhb deficient cells exhibit a metastatic phenotype as highlighted by increased individual cell migration (characterized by faster motility and increased persistence) as well as high invasive and adhesion abilities. This phenotype is associated with the modulation of Twist1, Twist2, Tcf3, Snai1, N-cadherin or Krt19 expression, reflecting an EMT-like reprogramming of cells. Krt19 is epigenetically silenced in Sdhb-deficient cells and re-expressed after treatment by the demethylating agent decitabine. Krt19 rescue by lentiviral transduction in Sdhb-deficient cells and Krt19 inhibition by RNA interference in wild-type cells were performed. Both studies revealed the involvement of KRT19 in the invasive phenotype by modulating collective and individual migration and cell/extra-cellular matrix adhesion properties. These findings underline the role of hypermethylation and EMT in the in vitro acquisition of metastatic properties, following SDHB loss of function.
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Loriot
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.|INSERM, U1021, CNRS UMR3347, Institut Curie, F-91405 Orsay, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Domingues
authors.affiliation: INSERM, U968, Institut de la vision, F-75012 Paris, France.|Université Pierre et Marie Curie Paris 06, F-75005 Paris, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Berger
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Menara
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Maëva
authors.initials: M
authors.lastname: Ruel
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Morin
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Luis-Jaime
authors.initials: LJ
authors.lastname: Castro-Vega
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, F-75013 Paris, France.
authors.forename: Éric
authors.initials: É
authors.lastname: Letouzé
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Martinelli
authors.affiliation: CEA, DSV, I2BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France.|CNRS, CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
authors.forename: Alexis-Pierre
authors.initials: AP
authors.lastname: Bemelmans
authors.affiliation: INSERM, U1021, CNRS UMR3347, Institut Curie, F-91405 Orsay, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, France.|Rare Adrenal Cancer Network-Cortico Médullosurrénale Tumeurs Endocrines, Institut National du Cancer, F-75014 Paris, France.
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D019439:Chromaffin Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D013385:Succinate Dehydrogenase
keywords: EMT; SDHB; keratin 19; metastasis; paraganglioma