Core A: Molecular Pathology Core

项目概要/摘要： 分子病理学核心的目标是：（i）为项目研究人员提供 获得高质量的，临床注释的人类膀胱肿瘤，代表了疾病的全谱， (ii)协助研究人员获取人膀胱肿瘤进行分子研究和类器官研究 生成，和（iii）协助膀胱肿瘤的形态学、组织病理学和基因组表征。 肿瘤，包括在基因工程小鼠模型（GEMM）中产生的那些。核心A将扮演一个中心 根据每个项目的要求，负责收集、注释、储存和分发人体组织，并将协助 与鼠和人类肿瘤和类器官的组织学，分子和基因组分析， 从模型系统到人尿路上皮癌的分子发现的验证。特别的科学焦点 核心A的任务是与项目调查人员合作，对项目的时间顺序进行分析， 人类膀胱癌中出现基因组改变。核心的目标是：目标1：获取和维护 尿路上皮肿瘤的生物储存库，反映了从早期非肿瘤到晚期肿瘤的所有疾病进展状态。 侵袭性肿瘤，肌肉浸润性原发性肿瘤转移性病变，这反映了种族 尿路上皮肿瘤患者的性别多样性。核心将与项目调查人员合作， 定义膀胱癌中突变事件的时间序列，重点关注 表观遗传调节因子，如KDM 6A和ARID 1A，以及与DNA修复和化疗相关的基因 响应，例如ERCC 2。核心还将构建膀胱标本的组织微阵列，特别是 那些已经被表征为基因组改变的，以促进验证关键分子发现， GEMM和人类类器官模型对人类膀胱癌的研究。目标2：提供专家 来自患者和小鼠膀胱肿瘤的组织病理学评价和分子表征。 核心蛋白A将在小鼠和人类尿路上皮肿瘤的分子表征中发挥关键作用， 分析最具代表性的肿瘤区域，并根据需要进行宏观或显微解剖 以富集肿瘤内容物或将非侵入性区域与侵入性区域或形态上不同的区域分离。芯A 还将协助项目研究人员进行肿瘤的基因组测序分析，以及 进行和解释H&E、免疫组织化学和原位杂交分析。 整合：每个项目将需要分子病理学核心的贡献，以实现其拟议的 研究目的。项目负责人将与核心团队合作，获取并处理成对的非侵入性/侵入性， 原发性/转移性样品和在患者疾病过程中不同时间收集的样品，以确定 在膀胱癌发病过程中出现基因组改变的时间。核心还将协助 GEMM类器官模型组织病理学形态学和分子表征。

Project Summary/Abstract: The objectives of the Molecular Pathology Core are: (i) to provide Program Project investigators with access to high-quality, clinically-annotated human bladder tumors that represent the full spectrum of the disease, (ii) to assist investigators with acquisition of human bladder tumors for molecular studies and organoid generation, and (iii) to assist with the morphologic, histopathologic, and genomic characterization of bladder tumors, including those that arise in genetically-engineered mouse models (GEMMs). Core A will play a central role in collecting, annotating, storing, and distributing human tissues as required for each Project, and will assist with histologic, molecular, and genomic analyses of murine and human tumors and organoids, and with the validation of molecular findings from model systems to human urothelial cancer. The particular scientific focus of Core A will be to work with Program investigators to pursue analysis of the temporal sequence in which genomic alterations arise in human bladder cancer. The Aims of the Core are: Aim 1: To acquire and maintain a biorepository of urothelial tumors that reflects all states of disease progression from early non- invasive tumors, to muscle-invasive primary tumors to metastatic lesions, and that reflects the ethnic and gender diversity of patients with urothelial tumors. The Core will work with Program investigators to define the temporal sequence of mutational events in bladder cancer, with a focus on the timing of mutations in epigenetic regulators, such as KDM6A and ARID1A, and genes associated with DNA repair and chemotherapy response, such as ERCC2. The Core will also construct tissue microarrays from bladder specimens, particularly those that have been characterized for genomic alterations, to facilitate validation of key molecular findings from studies of GEMMs and human organoid models to human bladder cancer. Aim 2: To provide expert histopathologic evaluation and molecular characterization of bladder tumors from patients and mice. Core A will play a key role in the molecular characterization of mouse and human urothelial tumors by selecting the most representative tumor regions to be analyzed and by performing macro- or microdissection as needed to enrich for tumor content or to separate non-invasive from invasive or morphologically distinct regions. Core A will also assist the Program investigators with genomic sequencing analyses of tumors, as well as with performing and interpreting H&E, immunohistochemical, and in situ hybridization assays. Integration: Each Project will require contribution from the Molecular Pathology Core to achieve their proposed research aims. Project Leaders will work with the Core to obtain and process paired non-invasive/invasive and primary/metastatic samples and samples collected at distinct times in a patient's disease course to define the timing at which genomic alterations arise during bladder cancer pathogenesis. The Core will also assist in the histopathologic morphologic and molecular characterization of GEMMs organoid models.