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 该提案的总体目标是从高度可访问的癌前病变中构建两个癌前病变图谱（PCA）， 对人类健康造成沉重负担的恶性疾病（一）一种是侧重于前 黑色素瘤病变到浸润性癌症和（ii）第二个从克隆性造血（CHIP）进展到 骨髓肿瘤这两种方法都涉及在正常和患病的小生境中扩增特定的克隆， 由免疫细胞和癌前细胞之间复杂的相互作用形成。由此产生的酶由 皮肤和血液起源癌前病变中心（PATCH中心）提供补充 技术挑战、科学发现的途径以及精确度发展的机遇 预防策略和治疗。在这两种情况下，关键目标都是精确地描述和理解 从癌前病变发展到恶性疾病的分子机制，以识别高风险 个人，优先考虑特定的疗法，并作为精确预防临床试验的基础。 这将通过使用high-plex PCR对单细胞基因型和细胞状态进行综合表征来实现。 横截面和良好控制的纵向患者队列的组织成像和组学表征。 目标1将建立一个行政核心，负责中心的科学管理，协调 在内部执行委员会的指导下， 三个小组委员会目标2将在病理学家、肿瘤学家的领导下建立一个生物标本股 和外科医生DFCI Pasquarello组织库将提供高度注释的血液学 用于CHIP的基于图像和组学表征的标本; BWH皮肤病理学组织库 将提供黑色素瘤前体的注释FFPE样本。这些服务还将在以下方面发挥关键作用： 前瞻性样本采集和分析。目标3将设立一个表征股， 肿瘤学家和病理学家进行和整合单细胞基因组学，多重流式细胞术和高， 使用两种方法的复合成像减少到中心内的实践：基于组织的循环 免疫荧光（t-CyCIF）和DNA交换成像（DEI）。特性描述股还将验证 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。 目标4将建立一个数据分析股，招募系统和计算生物学家和数据科学家， 管理数据采集、解释和可视化的各个方面。预计这将是最 Atlas项目的技术挑战方面。数据分析股将发布第一/第二阶段地图集， 在初步和最后阶段，以促进合作和众包的方法，以算法 发展由此产生的人类可浏览和机器可读的地图集预计将产生新的 科学发现，证明新技术的可行性和实用性，并有助于减少 危及生命的皮肤癌和血癌的发病率。