Project description:Using the adrenal gland as a model, we investigated the interplay between genetic Znrf3 inactivation and the aging microenvironment. We hypothesized that SF1-Cre-driven Znrf3 cKO mice would progress from adrenal hyperplasia to carcinoma with age. Unexpectedly, after an initial phase of hyperplasia, we found that Znrf3 cKO adrenals steadily regress over time. We demonstrate this phenotypic switch from hyperplasia to regression is driven by activation of cellular senescence and a subsequent senescence-associated secretory phenotype (SASP).
Project description:Aging markedly increases cancer risk, yet our mechanistic understanding of how aging influences cancer initiation is limited. Here we demonstrate that the loss of ZNRF3, an inhibitor of Wnt signaling that is frequently mutated in adrenocortical carcinoma, leads to the induction of cellular senescence that remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer in old animals. The effects are sexually dimorphic, with males exhibiting earlier senescence activation and a greater innate immune response, driven in part by androgens, resulting in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and increased susceptibility to metastatic cancer. Senescence-recruited myeloid cells become depleted as tumors progress, which is recapitulated in patients in whom a low myeloid signature is associated with worse outcomes. Our study uncovers a role for myeloid cells in restraining adrenal cancer with substantial prognostic value and provides a model for interrogating pleiotropic effects of cellular senescence in cancer.
Project description:Using single-cell RNA-sequencing (scRNA-seq), we characterize diverse immune cell infiltrates that remodel the tissue microenvironment following senescence activation in female Znrf3 cKO mice.
Project description:Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We defined the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and used genetic models to explore the developmental mechanisms yielding to macrophage diversity. We defined populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identified a female-specific subset with low MHC-II expression. In adulthood, monocyte recruitment dominated adrenal gland macrophage maintenance in female mice, while self-proliferation was more important in males. Adrenal gland macrophage sub-tissular distribution followed a sex-dimorphic pattern, with MHC-IIlow macrophages located at the border between the cortex and the medulla. Macrophage sex dimorphism depended on the presence of the cortical Xzone. Forcing X-zone maintenance in males, or its degradation in females, directly impacted the presence of MHC-IIlow macrophages. Adrenal gland macrophage depletion resulted in altered tissue homeostasis, modulated lipid- metabolism and decreased local aldosterone production during stress exposure. Overall, these data explain the heterogeneity of adrenal gland macrophages and point toward sexrestricted distribution and functions of these cells.
Project description:Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We defined the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and used genetic models to explore the developmental mechanisms yielding to macrophage diversity. We defined populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identified a female-specific subset with low MHC-II expression. In adulthood, monocyte recruitment dominated adrenal gland macrophage maintenance in female mice, while self-proliferation was more important in males. Adrenal gland macrophage sub-tissular distribution followed a sex-dimorphic pattern, with MHC-IIlow macrophages located at the border between the cortex and the medulla. Macrophage sex dimorphism depended on the presence of the cortical Xzone. Forcing X-zone maintenance in males, or its degradation in females, directly impacted the presence of MHC-IIlow macrophages. Adrenal gland macrophage depletion resulted in altered tissue homeostasis, modulated lipid- metabolism and decreased local aldosterone production during stress exposure. Overall, these data explain the heterogeneity of adrenal gland macrophages and point toward sexrestricted distribution and functions of these cells.
Project description:Sex estimation of human remains from demineralized blocks of tooth enamel by liquid chromatography tandem mass spectrometry (LC- MS/MS) and proteomic analysis of sexually dimorphic amelogenin peptides. The detection of the Y-isoform of amelogenin is used to estimate male sex. The combined signal intensity of the sexually dimorphic peptides from each samples of known sex is used to establish a statistical framework for the estimation of the female sex probability.
Project description:Moderate Endurance Exercise increases Arrhythmia Susceptibility and modulates Cardiac Structure and Function in a Sex Dimorphic manner.