Pre-cancer atlases of cutaneous and hematologic origin (PATCH Center)

皮肤和血液来源的癌前图谱（PATCH 中心）

• 批准号: 10252281
• 负责人: JON C. ASTER
• 金额: $ 97.48万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252281
• 关键词: Antibodies; Area; Atlases; Automobile Driving; Back; Benchmarking; Biological Assay; Biological Specimen Banks; Biopsy; Blood; Bone Marrow; Cancer Histology; Cell Line; Cells; Cellular Morphology; Clinical; Clinical Data; Code; Collaborations; Collection; Communication; Complex; Computer Vision Systems; Computers; Computing Methodologies; Cutaneous; DNA; DNA sequencing; Data; Data Analyses; Data Scientist; Databases; Development; Diagnosis; Disease; Disease Progression; Engineering; Enrollment; Ensure; FAIR principles; Fee-for-Service Plans; Flow Cytometry; Formalin; Foundations; Freezing; Funding; Genetic; Genomics; Genotype; Goals; Head; Health; Hematology; Hematopoiesis; Hematopoietic Neoplasms; Histologic; Human; Image; Immune; Immunofluorescence Immunologic; Incidence; Individual; Industrialization; Laboratories; Lead; Leadership; Lesion; Life; Link; Liquid substance; Malignant - descriptor; Malignant Neoplasms; Maps; Metadata; Methods; Molecular; Monitor; Myeloproliferative disease; Oncologist; Paraffin Embedding; Pathologist; Patients; Performance; Periodicity; Pharmacology; Phase; Physicians; Play; Positioning Attribute; Prevention strategy; Prevention therapy; Prevention trial; Prospective cohort; Protocols documentation; Readability; Reagent; Research Personnel; Risk; Running; Sampling; Scientist; Services; Skin Cancer; Software Engineering; Solid; Specimen; Standardization; Stromal Cells; Surgeon; System; Technology; Testing; Time; Time Series Analysis; Tissue Banks; Tissue imaging; Tissues; Tumor Tissue; Validation; Visualization; Visualization software; Work; algorithm development; base; cancer invasiveness; cell type; cohort; computing resources; crowdsourcing; data acquisition; data standards; data submission; data visualization; deep neural network; dimensional analysis; feature extraction; genetic analysis; high dimensionality; high risk; image visualization; individual patient; individualized prevention; insight; knowledge base; laser capture microdissection; machine learning method; melanoma; member; multiplexed imaging; neoplastic; new technology; premalignant; prevent; prevention clinical trial; prospective; skin lesion; tumor microenvironment

SUMMARY-ABSTRACT The overall goal of this proposal is to construct two pre-cancer atlases (PCAs) from highly accessible pre- malignant diseases that impose high burdens on human health (i) one focused on progression of pre- melanoma lesions to invasive cancer and (ii) a second on progression from clonal hematopoiesis (CHIP) to myeloid neoplasms. Both of these involve expansion of specific clones in normal and diseased niches as shaped by complex interactions among immune and pre-cancer cells. The resulting Atlases developed by the Center for Pre-cancer Atlases of Cutaneous and Hematologic Origin (PATCH Center) present complementary technical challenges, avenues to scientific discovery, and opportunities for the development of precision prevention strategies and therapies. The key goal in both cases is to precisely delineate and understand the molecular mechanisms driving progression from pre-malignant to malignant disease, to identify high risk individuals, prioritize particular therapies and serve as the foundation for precision prevention clinical trials. This will be achieved by integrated characterization of single cell genotype and cell states using high-plex tissue imaging and omic characterization of cross-sectional and well-controlled longitudinal patient cohorts. Aim 1 will establish an administrative core responsible for scientific management of the Center, coordination with HTAN members and dissemination of Atlases under the direction of an internal Executive Committee with three subcommittees. Aim 2 will establish a Biospecimen Unit under the leadership of pathologists, oncologists and a surgeon. The DFCI Pasquarello Tissue Repository will provide highly annotated hematological specimens for image-based and omic characterization of CHIP; the BWH dermatopathologic tissue repository will provide annotated FFPE samples for melanoma precursors. These services will also play a key role in prospective sample acquisition and analysis. Aim 3 will establish a Characterization Unit directed by an oncologist and pathologist to perform and integrate single-cell genomics, multiplex flow cytometry and high- plex imaging using two methods reduced to practice within the Center: tissue-based cyclic immunofluorescence (t-CyCIF) and DNA exchange imaging (DEI). The Characterization Unit will also validate reagents and associate all primary results with appropriate metadata, protocols and reagent specifications. Aim 4 will establish a Data Analysis Unit enlisting systems and computational biologists and data scientists to manage all aspects of data acquisition, interpretation and visualization. This is expected to be the most technically challenging aspect of the Atlas projects. The Data Analysis Unit will release Phase I/II atlases each in preliminary and final stages to facilitate collaborative and crowd-sourced approaches to algorithm development. The resulting human browsable and machine-readable atlases are expected to yield new scientific discoveries, demonstrate the feasibility and utility of new technologies and help to reduce the incidence of life-threatening cancers of the skin and blood.

摘要提取 该提案的总体目标是从高度易于访问的预 - 恶性疾病对人类健康施加了很大的负担（i），重点是 黑色素瘤病变对浸润性癌症，（ii）第二次从克隆造血（CHIP）发展为 髓样肿瘤。这两者都涉及在正常和患病壁ches中的特定克隆的扩展 由免疫和癌细胞之间的复杂相互作用形成。由 皮肤和血液学起源（斑块中心）的前癌前地图中心 技术挑战，科学发现的途径以及开发精度的机会 预防策略和疗法。在这两种情况下，关键目标是精确描述并了解 分子机制驱动从恶性疾病到恶性疾病的发展，以确定高风险 个人，优先考虑特定的疗法，并作为预防临床试验的基础。 这将通过使用高质量的单细胞基因型和细胞态的整合表征来实现这一点 组织成像和横截面和良好控制纵向患者队列的杂音表征。 AIM 1将建立负责该中心科学管理的行政核心 与HTAN成员一起，并在内部执行委员会的指导下传播地图集 三个小组委员会。 AIM 2将在病理学家，肿瘤学家的领导下建立一个生物循环单位 和外科医生。 DFCI Pasquarello组织存储库将提供高度注释的血液学 用于基于图像的芯片表征的标本； BWH皮肤病理组织存储库 将提供带注释的FFPE样品作为黑色素瘤前体。这些服务也将在 前瞻性样本获取和分析。 AIM 3将建立一个由 肿瘤学家和病理学家执行和整合单细胞基因组学，多重流式细胞仪和高 使用将两种方法降低为练习中心的plex成像：基于组织的循环 免疫荧光（T-Cycif）和DNA交换成像（DEI）。表征单元还将验证 试剂并将所有主要结果与适当的元数据，方案和试剂规格相关联。 AIM 4将建立一个数据分析单元，以吸引系统，计算生物学家和数据科学家 管理数据获取，解释和可视化的所有方面。预计这将是最大的 在技​​术上具有挑战性的Atlas项目方面。数据分析单元将释放第I/II期地图集 在初步和最后阶段，以促进算法的协作和众包方法 发展。预计由此产生的人浏览和机器可读地图集将产生新的 科学发现，证明了新技术的可行性和实用性，并有助于减少 威胁生命的皮肤和血液癌症的发生率。