EYES2022 ESE Young Endocrinologists and Scientists (EYES) 2022 Endocrine-related Cancer (11 abstracts)
Ablation of Znrf3 & Trp53 induces metastatic adrenocortical carcinoma in mice
Wilmouth JR J. 1 , Olabe J. 1 , Landwehr L. 3 , Pucheu L. 1 , Dufour D. 1 , Roucher-Boulez F. 2 , Lucas-Rodrigues C. 1 , Garcia-Garcia D. 1 , Damon-Soubeyrand C. 1 , Kroiss M. 3,4 , Fassnacht M. 3 , Lefrançois-Martinez A. 1 , Martinez A. 1 & Val P. 1
1Institut GReD (Genetics, Reproduction and Development), CNRS UMR 6293, Inserm 11 U1103, Université Clermont Auvergne, Endocrinology, signalling and cancer; 2Laboratoire de Biochimie et Biologie Moléculaire, 14 Groupement Hospitalier Est, Hospices Civils de Lyon, UM Pathologies Endocriniennes; 3University Hospital, University of Würzburg, Division of Endocrinology and Diabetes; 4LMU Klinikum, Department of Internal Medicine IV
Background: Adrenocortical carcinoma (ACC) is an aggressive cancer originating from steroidogenic cells within the adrenal cortex. Unfortunately, half of patients present with metastatic spread upon initial diagnosis, and there is no curative therapy for advanced disease. Genomic analysis has identified that the most aggressive subgroup of ACC patients have overlapping alterations in the WNT/β-catenin pathway and the p53/RB signaling pathway.
Objectives: Create a metastatic ACC mouse model based on patient genomic alterations.
Methods: We used SF1-Cre to inactivate both Znrf3, a negative regulator of the WNT/ β-catenin pathway, & Trp53, a potent tumor suppressor, in steroidogenic cells of the mouse adrenal cortex. The ROSA26mTmG reporter was included in the breeding scheme to track metastatic dissemination.
Results: By 6 months of age, mice with individual inactivation of Trp53 (PKO) or Znrf3 (ZKO) did not show tumor formation, while the combined inactivation of Trp53 & Znrf3 (DKO) resulted in aggressive carcinomas that metastasize to the lungs at a rate of 40.1%. Consistent with human patients, these tumors show significantly increased expression of established ACC aggressiveness markers Ki67 & EZH2. By subdividing the DKOs based on their ability to form distant metastasis (indolent vs metastatic), we found that metastatic DKOs are nonfunctioning, dedifferentiated tumors that exhibit massive upregulation of WNT/β-catenin signaling. Furthermore, these unique characteristics are maintained at distant secondary locations, suggesting their importance in the tumorigenic process.
Conclusions: These results establish that combined inactivation of Znrf3 & Trp53 in steroidogenic cells provides a habitable environment for the development of metastatic ACC. The timeline and consistent rate of metastasis in this mouse model highlights its importance for the study of metastatic ACC dissemination, immune-tumor interactions, and potential anti-cancer therapies.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more