The role of Znrf3 and the immune microenvironment in the development of adrenocortical tumorigenesis
J. Wilmouth Jr*a (M.), J. Olabea (Dr), KJ. Bashamb (Dr), L. Pucheua (Mlle), F. Roucher-Boulezc (Dr), C. Lucas-Rodriguesa (Dr), C. Damon-Soubeyranda (Mme), AM. Lefrançois-Martineza (Pr), A. Martineza (Dr), G. Hammerd (Pr), P. Vala (Dr)
a Institut Genetique Reproduction & Developpement CNRS UMR6293 INSERM U1103, Clermont-Ferrand, FRANCE ; b Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, ÉTATS-UNIS ; c Hospices Civils de Lyon, Biochimie Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Lyon, FRANCE ; d Endocrine Oncology Program, University of Michigan Rogel Cancer Center, Ann Arbor, ÉTATS-UNIS
Objective: Adrenocortical carcinoma (ACC) is an aggressive cancer that originates from steroidogenic cells within the adrenal cortex. The most common alteration in ACC patients is inactivation of the transmembrane E3 ubiquitin-ligase Zinc and Ring Finger 3 (ZNRF3), which is responsible for inhibiting the canonical WNT /Beta-catenin pathway. We show that inactivation of Znrf3 (ZKO) in the adrenal cortex results in an initial hyperplasia by 6-weeks, after which sexually dimorphic phenotypes arise.
Materials & Methods: Adrenal cortex specific ablation of Znrf3 & Trp53 was achieved by Cre/LoxP recombination technology.
Results: In males, but not females, Znrf3 inactivation induces senescence and release of senescence associated secretory phenotype (SASP) factors. This is associated with recruitment of macrophages (Mφ) that phagocytose neoplastic cells, which is associated with regression of hyperplasia. In ACC patients, ZNRF3 inactivation is frequently associated with mutations of TP53, a key inducer of senescence, suggesting that inhibition of senescence may be required for tumorigenesis to proceed. Preliminary data suggests that combined inactivation of Trp53 and Znrf3 (DKO) results in blunted senescence, reduced Mφ recruitment and acceleration of tumorigenesis, ultimately culminating with metastatic ACC development at 6 months.
Discussion: Our current aim is to use this metastatic ACC mouse model to highlight the role of Mφ in immunosurveillance and tumor inhibition within the adrenal cortex.
L’auteur n’a pas transmis de déclaration de conflit d’intérêt.