Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner

Abstract

Aging is a carcinogen that markedly increases cancer risk, yet we have limited mechanistic understanding of cancer initiation in aged cells. Here, we demonstrate induction of the hallmark aging process cellular senescence, triggered by loss of Wnt inhibitor ZNRF3, remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer. Detailed characterization reveals a striking sexual dimorphism. Males exhibit earlier senescence activation and a greater innate immune response. This results in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and are more prone to metastatic cancer. Senescence-recruited myeloid cells become increasingly depleted with advanced tumor progression, which is recapitulated in patients where a low myeloid signature is associated with worse outcome. Collectively, our study reveals a novel role for myeloid cells in restraining adrenal cancer progression with significant prognostic value, and provides a model for interrogating pleiotropic effects of cellular senescence in cancer.Graphical abstract created with BioRender.com

Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development

“…A recently posted BioRxiv preprint reports similar findings in a mouse model of Znrf3 inactivation (68). Although differences in genetic backgrounds resulted in a more pronounced immune response in females in their model than in ours, Warde and colleagues also showed that male Znrf3 KO adrenals mounted a profound macrophage-dependent antitumor response, further strengthening the findings reported here.…”

β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

“…Our data suggest that the cell originating CIMP-high ACC is one which relies on βcatenin and zF differentiation for sustained proliferation, perhaps a transit-amplifying ACTHresponsive cell of the upper zF which fails to proliferate in the setting of congenital adrenocortical EZH2 deficiency or β-catenin ablation (87,108). This is further supported by the demonstrations that combined β-catenin/cell cycle GOF generates zF-differentiated glucocorticoid producing ACC (22), and adrenocortical deficiency of negative Wnt pathway regulator ZNRF3 induces zF hyperplasia with eventual malignant transformation (109)(110)(111).…”

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

“…Our data suggest that the cell originating CIMP-high ACC is one which relies on β-catenin and zF differentiation for sustained proliferation, perhaps a transit-amplifying ACTH-responsive cell of the upper zF which fails to proliferate in the setting of congenital adrenocortical EZH2 deficiency or β-catenin ablation (Finco et al, 2018;Mathieu et al, 2018). This is further supported by the demonstrations that combined βcatenin/cell cycle GOF generates zF-differentiated glucocorticoid producing ACC (Borges et al, 2020), and adrenocortical deficiency of negative Wnt pathway regulator ZNRF3 induces zF hyperplasia with eventual malignant transformation (Basham et al, 2019;Warde et al, 2022;Wilmouth et al, 2022).…”