ECE2022 Poster Presentations Endocrine-Related Cancer (41 abstracts)
A metastatic ACC mouse model: Combined inactivation of Znrf3 & Tp53 results in consistent adrenocortical carcinoma formation
James Wilmouth 1 , Julie Olabe 2 , Laly Pucheu 2 , Roucher Florence 3 , Cecily Lucas Rodrigues 2 , Christelle Soubeyrand-Damon 2 , Kroiss Matthias 4,5 , Laura-Sophie Landwehr 4 , Martin Fassnacht 4 , Anne-Marie Lefrancois-Martinez 2 , Antoine Martinez 2 & Pierre Val 2
1iGReD UMR CNRS 6293, INSERM U1103, Clermont-Ferrand, France; 1 iGReD UMR CNRS 6293, INSERM U1103, Clermont-Ferrand, France; 3Hospices Civils de Lyon, Biochimie Biologie Moléculaire Grand Est - UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Lyon, France; 4Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Department of Internal Medicine I, Würzburg, Germany; 5LMU Klinikum, Department of Internal Medicine IV, Munich, Germany
Adrenocortical carcinoma (ACC) is an infrequent and aggressive cancer that originates from steroidogenic cells within the adrenal cortex. Half of patients present with metastatic spread at initial diagnosis, and to date, there is no curative therapy for advanced disease. Recent genomic analysis has established that the most aggressive subgroup of ACC patients have overlapping alterations in the WNT/B-catenin pathway and the p53/RB pathway. We therefore set out to develop a metastatic ACC mouse model based on patient genomic alterations. Using Cre loxP technology, we inactivated both Znrf3, a negative regulator of the WNT/beta-catenin pathway, & p53, a potent tumor suppressor, in steroidogenic cells. By 6 months of age, mice with individual inactivation of p53 (PKO) or Znrf3 (ZKO) did not show tumor formation, while the combined inactivation of p53 & Znrf3 (DKO) resulted in aggressive carcinomas that metastasize at a rate of 36.8%. Using the ROSA26mTmG reporter, we identified metastatic deposits in the lymph nodes, peritoneal cavity, lungs and liver of DKO mice. Importantly, metastatic DKOs show a significant increase in adrenal weight and Ki67 index, while having a significant decrease in overall survival. Furthermore, these tumors are hormonally inactive, representing a subtype of ACC that has not been previously established in available mouse models. Taken together, these results establish that combined inactivation of Znrf3 & p53 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.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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