PO.TB07.01 · 肿瘤生物学
利用整合了族群遗传决定因素的iPSC来源子宫内膜类器官对子宫内膜癌进行建模
Modeling endometrial cancer using iPSC-derived endometrial organoids integrating genetic determinants of ethnicity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：子宫内膜癌是发达国家最常见的妇科肿瘤，仅在美国其发病率就以每年每10万名女性28.3例的速度上升。该肿瘤起源于子宫内膜的腺上皮，通常通过侵袭间质和肌层进展。子宫内膜癌的发生受遗传突变（PTEN、TP53、错配修复基因）以及族群、环境和激素因素的影响。目前仍缺乏一种能够捕捉这些复杂因素、可扩展且具有生理相关性的人类子宫内膜癌模型。
方法与结果：我们建立了人诱导多能干细胞（iPSC）来源的子宫内膜类器官，作为研究子宫内膜癌早期机制（包括癌症起始和进展）的平台。我们首先采用不同的方案来构建子宫内膜样上皮和间质。将来自一名健康个体的人iPSC分化为上皮类器官，该类器官由具有上皮-间质杂合表型（Pan-CK+/VIM+）的早期Müllerian管样细胞（MDLC）组成。为促进子宫内膜身份，将上皮类器官与子宫内膜间质细胞共培养，并用模拟人月经周期的单周期甾体激素进行处理。免疫荧光染色显示类器官发育出腔上皮和腺样结构（KRT8+/PAX8+/CDH1+），周围环绕VIM+间充质细胞。子宫内膜类器官具有激素反应性，并表达子宫内膜的功能标志物，包括分泌蛋白PRL和IGFBP1。通过纳入来自不同族群背景个体的iPSC并引入致病性遗传变异，我们旨在揭示遗传变异和人群特异性因素如何促成子宫内膜癌的发生和进展。
结论：我们预期该模型将使我们能够研究子宫内膜癌的多因素促成因素，并支持识别早期疾病事件和治疗靶点。
查看英文原文 English abstract
BACKGROUND: Endometrial cancer is the most common gynecologic cancer in developed countries with an increasing incidence of 28.3 per 100,000 women per year in the United States alone. The cancer arises from the glandular epithelium of the endometrium and typically progresses by invading the stroma and myometrium. Development of endometrial cancer is influenced by genetic mutations (PTEN, TP53, mismatch repair genes), as well as ethnic, environmental, and hormonal factors. A scalable, physiologically relevant human model of endometrial cancer that captures these complex factors remains lacking.
METHODS & RESULTS: We have established human induced pluripotent stem cell ( iPSC)-derived endometrial organoids as a platform for studying the early mechanisms of endometrial cancer, including cancer initiation and progression. We first used different protocols to create endometrial-like epithelium and stroma. Human iPSCs from a healthy individual were differentiated into epithelial organoids consisting of early-stage Müllerian duct-like cells (MDLCs) with an epithelial-mesenchymal hybrid phenotype (Pan-CK+/VIM+). To promote endometrial identity, epithelial organoids were co-cultured with endometrial stromal cells and treated with a single cycle of steroid hormones mimicking the human menstrual cycle. Immunofluorescence staining showed the organoids developed luminal epithelial and glandular-like structure (KRT8+/PAX8+/CDH1+), surrounded by VIM+ mesenchymal cells. Endometrial organoids are hormone responsive and express functional markers of uterine endometrium, including the secreted proteins, PRL and IGFBP1. By incorporating iPSCs from individuals of diverse ethnic backgrounds and introducing pathogenic genetic variants, we aim to uncover how genetic variation and population-specific factors contribute to endometrial cancer development and progression.
CONCLUSIONS: We anticipate this model will enable us to study the multifactorial contributors to endometrial cancer and support the identification of early disease events and therapeutic targets.
利益披露 Disclosure
S. Chear, None..
S. Gayther, None..
K. Lawrenson, None.