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.与大多数癌症不同，肾上腺皮质癌（adrenocortical carcinomas, ACC）的女性发病率高于男性，但这种性别二态性的潜在机制仍不明晰。本研究发现，小鼠肾上腺皮质类固醇生成细胞中Znrf3的失活与呈性别二态性的肿瘤进展相关。尽管雌性基因敲除小鼠在18月龄时会出现转移性癌，但雄性基因敲除小鼠的肾上腺增生则会消退。这种雄性特异性表型与雄激素依赖的细胞衰老诱导、高吞噬性巨噬细胞的招募与分化（可清除衰老细胞）密切相关。与之相反，雌性小鼠的巨噬细胞招募过程被延迟且受到抑制，从而促进了侵袭性肿瘤的进展。一致的是，对TCGA-ACC数据集的分析显示，高吞噬性巨噬细胞在男性患者中更为富集，且与更好的预后相关。综上，本研究数据表明，高吞噬性巨噬细胞是肾上腺皮质癌性别二态性的关键调控因子，并将其确立为这种恶性癌症的新型治疗靶点。 本数据集分析了野生型对照小鼠，以及肾上腺皮质类固醇生成细胞中Znrf3条件性敲除的小鼠（Znrf3 cKO = Sf1-Cre;Znrf3F/F）的全肾上腺基因表达谱。研究在不同时间点采集肾上腺样本，以评估表型的动态变化；同时分别采集雌雄小鼠的肾上腺样本，以分析其性别二态性。野生型小鼠与Znrf3条件性敲除小鼠均为同窝出生。