The Mayo GBM Xenograft National Resource

Mayo胶质母细胞瘤（GBM）异种移植国家资源将为用户提供强大的动物模型，具有相应的表型和分子特征，概括了来自79例患者来源的异种移植（PDX）的人类GBM肿瘤的关键分子和组织学表型。这些肿瘤模型是在梅奥诊所通过将手术组织直接植入免疫功能低下的小鼠体内，然后将这些肿瘤在小鼠体内连续传代而成的。PDX模型高度代表了人类GBM肿瘤，并保留了源自人类肿瘤的复杂分子特征。这些高度转化和相关的模型已广泛应用于神经肿瘤学研究；Mayo GBM pdx被用于100多篇同行评议的手稿中，并且是37项nih资助的研究项目（包括16项ninds资助的研究项目）的关键试剂。作为对人类肿瘤样本丰富的多组学数据集（如癌症基因组图谱）的补充，本R24的目标是在我们的GBM PDX模型中提供类似水平的分子表征，并使数据免费提供给用户。对于这个大型PDX小组来说，全面的多组学数据的可用性至关重要，这使得用户能够很容易地确定最相关的肿瘤模型，用于他们的特定研究项目。为了实现这一目标，本研究中提出的RNAseq、总蛋白质组学和磷酸化蛋白质组学研究（Aim 1）将与我们的全外显子组测序和全甲基组研究相结合，以提供跨PDX面板的广泛分子表征。这些数据集将使用系统生物学方法进行整合，以识别严重解除管制的信号网络，这将帮助具有有限生物信息学经验的用户解释多组PDX特征（目标2）。我们将使用开源的cbiopportal软件（用于托管MSKCC的癌症基因组图谱数据）托管所有的PDX分子和表型特征，为具有强大的集成多基因组搜索功能的强大数据库提供用户友好的界面（目标3）。与此同时，Mayo GBM异种移植国家资源将建立早期传代肿瘤分析（DNA、RNA和蛋白质提取物）和冷冻或冷冻保存肿瘤样本的档案，以便分发给用户（目标4）。通过这种方式，为这个拟议的国家资源计划的Aims将显著提高高度表征的GBM PDX模型的可用性，用于整个神经肿瘤学社区的基础和转化研究。

The Mayo Glioblastoma (GBM) Xenograft National Resource will provide users with robust animal models, with corresponding phenotypic and molecular characterizations, that recapitulate key molecular and histologic phenotypes of human GBM tumors from a panel of 79 patient-derived xenografts (PDX). These tumor models were created at the Mayo Clinic by implanting surgical tissue directly into immunocompromised mice and then serially passaging these tumors in mice. The PDX models are highly representative of human GBM tumors and preserve the complex molecular features of the human tumors they were derived from. These highly translational and relevant models have been used widely in neuro-oncology research; the Mayo GBM PDXs are used in over 100 peer-reviewed manuscripts and are key reagents in 37 NIH-funded grants (including 16 NINDS-funded grants). As a complement to the rich multi-omic data sets available on human tumor samples (e.g., The Cancer Genome Atlas), the goal of this R24 is to provide a similar level of molecular characterization across our GBM PDX models and make the data freely-available for Users. Availability of comprehensive multi-omic data for this large PDX panel is critically important to allow Users to readily identify the most relevant tumor model(s) for use in their specific research projects. Towards this goal, the RNAseq, total- and phospho-proteomics studies proposed in this study (Aim 1) will be combined with our whole-exome sequencing and whole methylome studies to provide a broad molecular characterization across the PDX panel. These datasets will be integrated using systems biology approaches to identify critically deregulated signaling networks, which will help Users with limited bioinformatics experience interpret the multi-omic PDX characterizations (Aim 2). We will host all of the PDX molecular and phenotypic characterizations using the open-source cBioPortal software (used to host The Cancer Genome Atlas data at MSKCC) to provide a user-friendly interface to a powerful database with robust integrative multi-omic search capabilities (Aim 3). In parallel, the Mayo GBM Xenograft National Resource will develop an archive of early-passage tumor analytes (DNA, RNA, and protein extracts) and frozen or cryopreserved tumor samples for distribution to Users (Aim 4). In this way, the Aims planned for this proposed National Resource will significantly enhance the availability of highly characterized GBM PDX models for use in basic and translational research across the neuro-oncology community.