Department of Cellular and Molecular Medicine, University of Arizona College of Medicine, Tucson, AZ 85721, USA.
Center for Biomedical Informatics and Biostatistics, University of Arizona Health Sciences, Tucson, AZ 85721, USA.
Cells. 2022 Oct 23;11(21):3344. doi: 10.3390/cells11213344.
(1) Background: Cushing's disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery. Current surgical remission rates reported in only 56% of patients depending on several criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies make CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of relevant human model systems that recapitulate the cellular composition of PitNET microenvironment. (2) Methods: human pituitary tumor tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). (3) Results: hPITOs generated from corticotroph, lactotroph, gonadotroph, and somatotroph tumors exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient's tumor was validated by comparing the neuropathology report to the expression pattern of PitNET specific markers, using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each tumor subtype. Generation of induced pluripotent stem cells (iPSCs) from a CD patient carrying germline mutation CDH23 exhibited dysregulated cell lineage commitment. (4) Conclusions: The human pituitary neuroendocrine tumor organoids represent a novel approach in how we model complex pathologies in CD patients, which will enable effective personalized medicine for these patients.
（1）背景：库欣病（CD）是一种严重的内分泌紊乱疾病，由促肾上腺皮质激素（ACTH）分泌的垂体神经内分泌肿瘤（PitNET）引起，刺激肾上腺过度产生皮质醇。长期暴露于过量皮质醇对健康有不利影响，包括增加中风率、糖尿病、肥胖、认知障碍、焦虑、抑郁和死亡。CD 的一线治疗是垂体手术。根据几项标准，目前仅报道了 56%的患者达到手术缓解。随后的二线药物治疗的特异性差、耐受性差和疗效低，使得 CD 成为医学治疗的挑战。阻碍特异性药物治疗发展的一个主要限制是缺乏能够重现 PitNET 微环境细胞组成的相关人类模型系统。（2）方法：从 CD 患者的经蝶窦手术中采集人垂体肿瘤组织以生成类器官（hPITOs）。（3）结果：从促皮质素细胞瘤、催乳素细胞瘤、促性腺激素细胞瘤和生长激素细胞瘤生成的 hPITOs 在个体患者之间和亚型之间的类器官系之间表现出形态多样性。通过比较神经病理学报告和 PitNET 特异性标志物的表达模式，使用光谱流式细胞术和外显子组测序，验证了类器官系与患者肿瘤之间细胞谱系的相似性。高通量药物筛选显示了 hPITOs 在每种肿瘤亚型中的患者特异性药物反应。从携带种系突变 CDH23 的 CD 患者中生成诱导多能干细胞（iPSCs）表现出细胞谱系失调的定向。（4）结论：人类垂体神经内分泌肿瘤类器官代表了我们在 CD 患者中模拟复杂病理的新方法，这将为这些患者提供有效的个性化药物治疗。
