title: From Nf1 to Sdhb knockout: Successes and failures in the quest for animal models of pheochromocytoma.
abstract: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors characterized by a high frequency of hereditary forms. Based on transcriptome classification, PPGL can be classified in two different clusters. Cluster 1 tumors are caused by mutations in SDHx, VHL and FH genes and are characterized by a pseudohypoxic signature. Cluster 2 PPGL carry mutations in RET, NF1, MAX or TMEM127 genes and display an activation of the MAPK and mTOR signaling pathways. Many genetically engineered and allografted mouse models have been generated these past 30 years to investigate the mechanisms of PPGL tumorigenesis and test new therapeutic strategies. Among them, only Cluster 2-related models have been successful while no Cluster 1-related knockout mouse was so far reported to develop a PPGL. In this review, we present an overview of existing, successful or not, PPGL models, and a description of our own experience on the quest of Sdhb knockout mouse models of PPGL.
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lepoutre-Lussey
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Thibault
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Buffet
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center, 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 Center, 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 d'anatomo-pathologie, F-75015 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.affiliation: INSERM, UMR1141, Hôpital Robert Debré, F-75019 Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.affiliation: INSERM, UMR1141, Hôpital Robert Debré, F-75019 Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France; Metabolic Biochemistry, Hôpital Necker-Enfants Malades, Paris, France; INSERM, Unit 1124, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France; Metabolic Biochemistry, Hôpital Necker-Enfants Malades, Paris, France; INSERM, Unit 1124, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Janin
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center, 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: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Trapman
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center, 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.
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France. Electronic address: judith.favier@inserm.fr.
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000818:Animals; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D025542:Neurofibromin 1; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase
keywords: Chromaffin cells; Genetically engineered mouse; Knockout; Pheochromocytoma; Xenograft