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Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development.

ABSTRACT: Unlike most cancers, adrenocortical carcinomas (ACCs) are more frequent in women than in men, but the underlying mechanisms of this sexual dimorphism remain elusive. Here, we show that inactivation of Znrf3 in the mouse adrenal cortex, recapitulating the most frequent alteration in ACC patients, is associated with sexually dimorphic tumor 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 tumor progression. Consistently, analysis of TCGA-ACC data shows that phagocytic macrophages are more prominent in men and are associated with better prognosis. Together, these data show that phagocytic macrophages are key players in the sexual dimorphism of ACC that could be previously unidentified allies in the fight against this devastating cancer.

SUBMITTER: Wilmouth JJ

PROVIDER: S-EPMC9565812 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development.

Wilmouth James J JJ Olabe Julie J Garcia-Garcia Diana D Lucas Cécily C Guiton Rachel R Roucher-Boulez Florence F Dufour Damien D Damon-Soubeyrand Christelle C Sahut-Barnola Isabelle I Pointud Jean-Christophe JC Renaud Yoan Y Levasseur Adrien A Tauveron Igor I Lefrançois-Martinez Anne-Marie AM Martinez Antoine A Val Pierre P

Science advances 20221014 41

Unlike most cancers, adrenocortical carcinomas (ACCs) are more frequent in women than in men, but the underlying mechanisms of this sexual dimorphism remain elusive. Here, we show that inactivation of <i>Znrf3</i> in the mouse adrenal cortex, recapitulating the most frequent alteration in ACC patients, is associated with sexually dimorphic tumor progression. Although female knockouts develop metastatic carcinomas at 18 months, adrenal hyperplasia regresses in male knockouts. This male-specific p ...[more]

PMID: 36240276

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Project description:As sex determines mammalian development, understanding the nature and developmental dynamics of the sexually dimorphic transcriptome is important. To explore this, we generated 72 genome-wide RNA-seq profiles from mouse eight-cell embryos, late gestation and adult livers, together with 4 ground-state pluripotent embryonic (ES) cell lines from which we generated both RNA-seq and multiple ChIP-seq profiles. We complemented this with previously published data to yield 5 snap-shots of pre-implantation development, late-gestation placenta and somatic tissue and multiple adult tissues for integrative analysis. We define a high-confidence sex-dimorphic signature of 56 genes in eight-cell embryos. Sex-chromosome-linked components of this signature are largely conserved throughout pre-implantation development and ES cells, whilst the autosomal component is more dynamic. Sex-biased gene expression is reflected by enrichment for activating and repressive histone modifications. The eight-cell signature is largely non-overlapping with that defined from fetal liver, neither was it correlated with liver or other adult tissues analysed. Fetal and adult liver gene expression signatures are also substantially different, yet a core set of common genes showing modest dimorphic expression was identified. Dramatic sex-specific expression of olfactory receptors was found in fetal liver. Sex-biased expression differences unique to adult liver were enriched for growth hormone-responsiveness. The majority of sex-chromosome based differences identified from eight-cell embryos are also present in placenta but not somatic tissue at the same gestational age. This systematic study identifies three distinct phases of sex dimorphism throughout mouse development, and has significant implications for understanding the developmental origins of sex-specific phenotypes and disease in mammals. Examination of the sexual dimorphisim during developmental stages of 8 Cell, Es Cell, Fetal Liver and Adult Liver

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Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development.

Publications

Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development.

Similar Datasets

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