WASHINGTON UNIVERSITY HUMAN TUMOR ATLAS RESEARCH CENTER

项目摘要/摘要 癌症研究的不同领域已经取得进展，现在可以有意义地整合 跨分子、细胞和组织领域的研究数据和临床信息 癌症肿瘤动力学的详细图像，包括癌症治疗和治疗期间的时空细节 进步。华盛顿大学医学院(WUSM)和The Siteman的医生和研究人员 癌症中心(WUSM-SCC)是癌症相关子学科的长期领导者，包括基因组学， 蛋白质组学、成像、功能表征、病理学、临床试验和临床护理。WUSM-SCC是一种 NCI指定的综合癌症中心，每年接待约9000名新的癌症患者。在基础上建设 我们的专业知识、成熟的基础设施、庞大的患者群体和非凡的机构承诺，我们 建议在华盛顿大学人类肿瘤图谱研究中心(WU-HTARC)内建立 美国国立卫生研究院人类肿瘤分析网络(Htan)。 我们将专注于为相关的三种高优先级癌症类型生成特定于器官的人类肿瘤图谱 预后极差：三阴性乳腺癌(TNBC)、胶质母细胞瘤(GBM)和胰腺癌 导管腺癌(PDAC)。总的来说，我们将分析从空间上收集的约1,600-2,000个样本 300-375例患者临床治疗过程中不同时间点和不同地点的分离分析 (从约750名招募的患者中挑选)，在项目期间。除了标准的组织病理学 分析，大量DNA/RNA测序，蛋白质组学，和临床成像等，我们将进行尖端， 综合分析，包括单细胞RNA-Seq(scRNA-Seq)、多重免疫荧光蛋白 定位(MxIF)、飞行时间质谱仪/细胞术(CyTOF)、细胞特性、代谢组学 分析、创新成像和3-D建模。 我们已经建立了涵盖上述领域的基础设施，从样品采购 (生物质化股)、多学科分析单元(定性股)和分析管道(数据 分析单位)。这项研究产生的数据将对揭示肿瘤的克隆进化有价值 从纵向采集的标本中提取细胞并重建涉及非肿瘤细胞的肿瘤生态系统 和脱细胞结构。随着时间的推移，我们的地图集将在3D级别进行全面的数据集成，提供 史无前例的3种癌症类型的4D模型。我们已建立的基础设施和持续的努力 将新技术融入组学、成像和信息学，将有助于确保我们的地图集将成为 最先进的技术，充分利用这些领域的最新进展，并将继续发展超越 试点阶段，以促进癌症研究和改善临床护理。 拟议的图谱针对一系列至关重要的临床问题，包括具有 长期以来一直是GBM治疗的一个挑战，也是BRCA/TNBC和PDAC的一个重要临床问题 其中少数族裔人口受到的影响不成比例。其他重点是BRCA对 化疗、PDAC转移和GBM局部复发与治疗耐药有关。这些 图谱可以在泛癌分析中相互参照。我们还将寻求与任何预 癌症图谱(PCA)中心研究这些疾病类型，以最大限度地提高研究的时间连续性 这些癌症。选定的三种癌症之间的相似和不同将提供协同作用 也将使我们在地图集建设中积累有价值的知识，为其他人提供参考 癌症类型。我们中心获得的数据、标本和经验将与Htan和 更广泛的研究社区，以促进个性化癌症药物的下一个重要发现。

Project Summary/Abstract Diverse areas of cancer research have progressed to the point that it is now feasible to meaningfully integrate research data and clinical information across the molecular, cellular, and tissue realms into a larger, more detailed picture of the onco-dynamics of cancer, including spatial-temporal details during cancer treatment and progression. Physicians and researchers at Washington University School of Medicine (WUSM) and the Siteman Cancer Center (WUSM-SCC) are longtime leaders in the allied sub-disciplines of cancer, including genomics, proteomics, imaging, functional characterization, pathology, clinical trials, and clinical care. WUSM-SCC is an NCI-designated Comprehensive Cancer Center, which sees ~9,000 new cancer patients annually. Building on our expertise, established infrastructure, large patient population, and extraordinary institutional commitment, we propose to develop the Washington University Human Tumor Atlas Research Center (WU-HTARC) within the NIH Human Tumor Analysis Network (HTAN). We will focus on generating organ-specific human tumor atlases for three high priority cancer types associated with exceptionally poor prognosis: the triple negative breast cancer (TNBC), glioblastoma (GBM), and pancreatic ductal adenocarcinoma (PDAC). Collectively, we will analyze ~1,600-2000 samples collected from spatially separated locations and at different time points along the clinical treatment course from 300-375 patients (selected from ~750 recruited patients) for the duration of the project. In addition to standard histopathological analyses, bulk DNA/RNA sequencing, proteomics, and clinical imaging, etc., we will conduct cutting-edge, comprehensive analyses, including single cell RNA-Seq (scRNA-Seq), multiplexed immunofluorescent protein localization (MxIF), mass cytometry/Cytometry by Time of Flight (CyTOF) cellular characterization, metabolomics analysis, innovative imaging, and 3-D modeling. We have established infrastructure covering the aforementioned areas, from specimen procurement (Biospecimen Unit), to multidisciplinary analyses modules (Characterization Unit), and to analysis pipelines (Data Analysis Unit). Data generated from this study will be valuable for revealing the clonal evolution of the tumor cells from longitudinally collected specimens and to reconstruct the tumor ecosystem involving non-cancer cells and acellular structures. Our atlases will have comprehensive data integration at the 3D level over time, providing unprecedented 4D models for the 3 selected cancer types. Our established infrastructure and continuous efforts in incorporating new technologies in omics, imaging, and informatics, will help ensure our atlases will be the state-of-the-art, taking full advantage of the latest progress in these fields and will continue to evolve beyond the pilot phase to facilitate cancer research and improve clinical care. The proposed atlases target a set of critically important clinical questions, including tumor resistance that has long been a challenge for GBM treatment and also an important clinical problem in BRCA/TNBC and PDAC, in which minority populations are disproportionately affected. Other emphases are BRCA response/resistance to chemotherapy, PDAC metastasis, and GBM local recurrence in conjunction with resistance to therapy. These atlases can cross reference each other for pan-cancer analyses. We will also seek to cooperate with any Pre- Cancer Atlas (PCA) centers studying these disease types to maximize the temporal continuity of research on these cancers. The similarities and differences among the three selected cancer types will provide synergy among the three atlases and will also allow us to accumulate valuable knowledge in atlas building for other cancer types. The data, specimens, and experience gained by our center will be shared with HTAN and the broader research community to foster the next important discoveries in personalized cancer medicine.