Core 2: Human Specimen and Organic Core (HSO Core)

项目概要-核心2：人体标本和类器官核心 诊断为胰腺导管腺癌（PDA）的患者通常对治疗干预无效 或迅速产生抗药性。为了研究治疗抗性的机制，组装的P01 研究小组将利用PDA患者来源的大型和代表性的三维类器官队列 模型（PDO）。类器官准确地概括了基因组、转录组和表型特征 的人PDA，并能够在异质性患者队列中预测药物反应。人类 标本和类器官核心（HSO核心）将有助于阐明耐药机制， 与每个研究项目的合作。HSO核心将测试许多新的治疗组合， 确定有效的协同战略。核心将提供一个强大的患者源性器官型 用于离体机理研究的肿瘤切片平台。此外，HSO核心将产生类器官共培养物， 与关键的基质细胞，并将开发类器官的基因工程小鼠（GEM）模型， 自发性PDA HSO核心的总体目标是支持每个项目的发现和验证 有效的治疗策略来克服治疗抵抗。为了实现这一目标，HSO核心有三个 目标。在目标1中，核心将提供方法论专业知识和为每个人量身定制的有价值的PDO模型 个别项目。包括恩替司他（项目1）和ULK 1/2等药物的新型治疗组合 抑制剂（项目3）将使用药效分型试验进行分析， 类器官的异质群组。将对各种组合进行评估，并以数学方式定义协同作用。 将利用现有的DNA/RNA测序数据集来发现药物敏感性的预测特征 和抵抗在目标2中，核心将提供一种器官型活肿瘤切片模型， 动脉导管未闭的肿瘤和间质细胞区室。HSO核心开发的方法允许 离体培养长达7天，使得能够扰动和表征细胞到细胞信号传导网络。 此外，核心将开发共培养系统，将上皮类器官，成纤维细胞和免疫细胞结合在一起。 与项目2合作。最后，在目标3中，核心将与鼠标模型核心合作， 从以前不可用的GEM模型中产生小鼠源性类器官，并开发类器官资源 促进研究项目和核心项目的工作流程。

PROJECT SUMMARY – Core 2: Human Specimen and Organoid Core Patients diagnosed with pancreatic ductal adenocarcinoma (PDA) often fail to respond to therapeutic intervention or rapidly develop resistance to treatment. To study mechanisms of therapeutic resistance, the assembled P01 research team will utilize a large and representative cohort of PDA patient-derived three-dimensional organoid models (PDOs). Organoids accurately recapitulate the genomic, transcriptomic, and phenotypic characteristics of human PDA and enable predictive profiling of drug response in a heterogenous patient-cohort. The Human Specimen and Organoid Core (HSO Core) will facilitate the elucidation of mechanisms of resistance in collaboration with each Research Project. The HSO Core will test numerous novel therapeutic combinations to determine effective and synergistic strategies. The Core will provide a powerful patient-derived organotypic tumor slice platform for ex vivo mechanistic studies. In addition, the HSO Core will generate organoid co-cultures with key stromal cells and will develop organoids from genetically engineered mouse (GEM) models that develop spontaneous PDA. The overall goal of the HSO Core is to support each Project in the discovery and validation of effective therapeutic strategies to overcome treatment resistance. To accomplish this, the HSO Core has three Aims. In Aim 1, The Core will provide methodology expertise and valuable PDO models tailored to each individual Project. Novel therapeutic combinations that include drugs such as Entinostat (Project 1) and ULK1/2 inhibitors (Project 3) will be profiled using a pharmacotyping assay that takes advantage of the Core’s heterogenous cohort of organoids. Combinations will be evaluated and synergies mathematically defined. Existing DNA/RNA-sequencing datasets will be leveraged to discover predictive signatures of drug sensitivity and resistance. In Aim 2, the Core will provide access to an organotypic living tumor slice model that preserves the neoplastic and stromal cellular compartments of PDA. Methodologies developed by the HSO Core allow for ex vivo culture up to 7 days, enabling the perturbation and characterization of cell to cell signaling networks. Further, the Core will develop co-culture systems that incorporate epithelial organoids, fibroblasts, and immune cells in collaboration with Projects 2. Finally in Aim 3, the Core will collaborate with the Mouse Models Core to generate mouse-derived organoids from previously unavailable GEM models and develop organoid resources to facilitate the workflow of the Research Projects and Cores.