title: P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model.
abstract: Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Pan-genomic analyses identified p53/Rb and WNT/β-catenin signaling pathways as main contributors to the disease. However, isolated β-catenin constitutive activation failed to induce malignant progression in mouse adrenocortical tumors. Therefore, there still was a need for a relevant animal model to study ACC pathogenesis and to test new therapeutic approaches. Here, we have developed a transgenic mice model with adrenocortical specific expression of SV40 large T-antigen (AdTAg mice), to test the oncogenic potential of p53/Rb inhibition in the adrenal gland. All AdTAg mice develop large adrenal carcinomas that eventually metastasize to the liver and lungs, resulting in decreased overall survival. Consistent with ACC in patients, adrenal tumors in AdTAg mice autonomously produce large amounts of glucocorticoids and spontaneously activate WNT/β-catenin signaling pathway during malignant progression. We show that this activation is associated with downregulation of secreted frizzled related proteins (Sfrp) and Znrf3 that act as inhibitors of the WNT signaling. We also show that mTORC1 pathway activation is an early event during neoplasia expansion and further demonstrate that mTORC1 pathway is activated in ACC patients. Preclinical inhibition of mTORC1 activity induces a marked reduction in tumor size, associated with induction of apoptosis and inhibition of proliferation that results in normalization of corticosterone plasma levels in AdTAg mice. Altogether, these data establish AdTAg mice as the first preclinical model for metastatic ACC.
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.|Centre Hospitalier Universitaire, Endocrinology Diabetology &Metabolic Diseases Department, School of Medicine, Clermont-Ferrand, France.
authors.forename: M
authors.initials: M
authors.lastname: Batisse-Lignier
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: I
authors.initials: I
authors.lastname: Sahut-Barnola
authors.affiliation: Department of Pathology, Reference Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.|Department of Pathology, Hôpital Pitié-Salpêtrière, Université Pierre &Marie Curie, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Tissier
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: T
authors.initials: T
authors.lastname: Dumontet
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: M
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: C
authors.initials: C
authors.lastname: Drelon
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Pointud
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: C
authors.initials: C
authors.lastname: Damon-Soubeyrand
authors.affiliation: Centre Hospitalier Universitaire, Department of Biochemistry and Molecular Biology, Clermont-Ferrand, France.
authors.forename: G
authors.initials: G
authors.lastname: Marceau
authors.affiliation: Department of Anatomopathology, Clermont-Ferrand Hospital, Clermont-Ferrand, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Kemeny
authors.affiliation: Department of Pathology, Reference Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.|Institut Cochin, Université Paris Descartes, INSERM U1016, CNRS UMR8104, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.|Centre Hospitalier Universitaire, Endocrinology Diabetology &Metabolic Diseases Department, School of Medicine, Clermont-Ferrand, France.
authors.forename: I
authors.initials: I
authors.lastname: Tauveron
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: P
authors.initials: P
authors.lastname: Val
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.affiliation: CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France.
authors.forename: A-M
authors.initials: AM
authors.lastname: Lefrançois-Martinez
mesh_terms: D018268:Adrenocortical Carcinoma / Q000473:pathology*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000502:physiology; D009362:Neoplasm Metastasis; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: D000952:Antigens, Polyomavirus Transforming; D046912:Multiprotein Complexes; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus