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P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model

Oncogene volume 36, pages 4445–4456 (2017)Cite this article

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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.

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Acknowledgements

We thank Lucile Mounier for technical assistance and Sandrine Plantade, Khirredine Ouchen and Philippe Mazuel for animal care. Tissue analyses were performed at Anipath Clermont core facility. This work was supported by Université Blaise Pascal, Université d′Auvergne, CNRS, INSERM, Agence National de la Recherche (grant ANR-14-CE12-0007), grants from Fondation ARC pour la Recherche sur le Cancer (PJA 20141201894) and from La Fondation de France. We thank the Cochin tumor bank and COMETE (COrtico MEdullo Tumeurs Endocrines) network for the provision of ACA and ACC tissue samples.

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Author notes

  1. M Batisse-Lignier and I Sahut-Barnola: These authors contributed equally to this work.

Authors and Affiliations

  1. CNRS UMR6293, GReD, INSERM U1103, Université Clermont Auvergne, Aubière, France

    M Batisse-Lignier, I Sahut-Barnola, T Dumontet, M Mathieu, C Drelon, J-C Pointud, C Damon-Soubeyrand, I Tauveron, P Val, A Martinez & A-M Lefrançois-Martinez

  2. Endocrinology Diabetology & Metabolic Diseases Department, Centre Hospitalier Universitaire, School of Medicine, Clermont-Ferrand, France

    M Batisse-Lignier & I Tauveron

  3. Department of Pathology, Reference Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

    F Tissier & J Bertherat

  4. Department of Pathology, Hôpital Pitié-Salpêtrière, Université Pierre & Marie Curie, Paris, France

    F Tissier

  5. Department of Biochemistry and Molecular Biology, Centre Hospitalier Universitaire, Clermont-Ferrand, France

    G Marceau

  6. Department of Anatomopathology, Clermont-Ferrand Hospital, Clermont-Ferrand, France

    J-L Kemeny

  7. Institut Cochin, Université Paris Descartes, INSERM U1016, CNRS UMR8104, Paris, France

    J Bertherat

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Batisse-Lignier, M., Sahut-Barnola, I., Tissier, F. et al. P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model. Oncogene 36, 4445–4456 (2017). https://doi.org/10.1038/onc.2017.54

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