Kinetic comparative analysis of gene expression in whole adrenal glands from Znrf3 cKO and control mice

Unlike most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Here, we show that inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Although female knockouts develop metastatic carcinomas at 18 months, adrenal hyperplasia regresses in male knockouts. This male-specific phenotype is associated with androgen-dependent induction of senescence, recruitment and differentiation of highly phagocytic macrophages that clear-out senescent cells. In contrast, in females, macrophage recruitment is delayed and dampened, which allows for aggressive tumour progression. Consistently, analysis of TCGA-ACC data shows that phagocytic macrophages are more prominent in men and associated with better prognosis. Altogether, these data show that phagocytic macrophages are key players in the sexual dimorphism of ACC and establish them as novel therapeutic targets for this devastating cancer. These data analyse gene expression in whole adrenals from wild-type control mice and mice with conditionnal ablation of Znrf3 (Znrf3 cKO = Sf1-Cre;Znrf3F/F) in steroidogenic cells of the adrenal cortex. Adrenals were collected at different timepoints to evaluate kinetic evolution of the phenotype and in both males and females to evaluate sexual dimorphism. Wild-type and Znrf3 cKO mice were littermates.