PDF(Pubmed)
Abstract：
BACKGROUND: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood.
METHODS: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours.
RESULTS: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response.
CONCLUSIONS: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues.
BACKGROUND: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.
METHODS: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours.
RESULTS: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response.
CONCLUSIONS: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues.
BACKGROUND: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.
摘要：
背景：人类肾上腺皮质由三个功能和结构不同的层组成；肾小球带，束状带(ZF)，和网状带(zR)，并以特定的方式产生肾上腺类固醇激素；醛固酮，皮质醇,和肾上腺雄激素,分别。产生皮质醇的腺瘤（CPA）主要是由于与蛋白激酶A途径相关的体细胞突变而发生的。然而,肾上腺皮质细胞获得基因突变后如何发展，仍然知之甚少。
方法：我们将详细的组织病理学研究与遗传学、RNA测序，与人类肾上腺皮质肿瘤相邻的肾上腺皮质的空间分辨转录组（SRT）分析。
结果：组织病理学分析显示肾上腺皮质结节状结构，表现出两层zF和zR样结构。结节结构带有GNAS体细胞突变，被称为注册会计师的驱动突变，并赋予细胞增殖和自主类固醇生成能力，我们称之为产生类固醇的结节（SPN）。RNA测序与SRT分析表明，zF样结构的扩展有助于CPAs的形成，而zR样结构的特征是巨噬细胞介导的免疫反应。
结论：我们假设注册会计师来自前兆病变，SPNs,其中两个不同的细胞群可能对肾上腺皮质肿瘤发生有不同的贡献。我们的数据还为人类肾上腺皮质组织分层结构的分子机制提供了线索。
背景：KAKENHI，上原纪念基金会,大和证券健康基金会，KaibaraMorikazu医学科学促进基金会，Secom科学技术基金会，ONO医学研究基金会,和日本应用酶学基金会。
方法：我们将详细的组织病理学研究与遗传学、RNA测序，与人类肾上腺皮质肿瘤相邻的肾上腺皮质的空间分辨转录组（SRT）分析。
结果：组织病理学分析显示肾上腺皮质结节状结构，表现出两层zF和zR样结构。结节结构带有GNAS体细胞突变，被称为注册会计师的驱动突变，并赋予细胞增殖和自主类固醇生成能力，我们称之为产生类固醇的结节（SPN）。RNA测序与SRT分析表明，zF样结构的扩展有助于CPAs的形成，而zR样结构的特征是巨噬细胞介导的免疫反应。
结论：我们假设注册会计师来自前兆病变，SPNs,其中两个不同的细胞群可能对肾上腺皮质肿瘤发生有不同的贡献。我们的数据还为人类肾上腺皮质组织分层结构的分子机制提供了线索。
背景：KAKENHI，上原纪念基金会,大和证券健康基金会，KaibaraMorikazu医学科学促进基金会，Secom科学技术基金会，ONO医学研究基金会,和日本应用酶学基金会。
