Molecular, Cellular, and Tissue Characterization Unit

分子、细胞和组织表征单元

• 批准号: 9627277
• 负责人: Steven M. Dubinett
• 金额: $ 110.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 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/9627277
• 关键词: Address; Adenocarcinoma; Appearance; Atlases; Biological Assay; Biopsy; Cell Nucleus; Cells; Cellular Morphology; Clinical; Collection; Cross-Sectional Studies; Cytotoxic T-Lymphocytes; DNA sequencing; Data; Data Analyses; Data Quality; Detection; Development; Disease; Disease Progression; Ecosystem; Evolution; Freezing; Fresh Tissue; Gene Expression; Imagery; Imaging technology; Immune; Immune response; Immunofluorescence Immunologic; In Situ; Intercept; Intervention; Investigation; Lesion; Ligation; Longitudinal prospective study; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Molecular; Multiplexed Ion Beam Imaging; Mutation; Nucleotides; Operative Surgical Procedures; Outcome; Pathogenesis; Phase; Phenotype; Premalignant; Premalignant Cell; Prevention; Prospective cohort; RNA; Research; Research Personnel; Resolution; Retrospective cohort; Sampling; Specimen; Splint Device; Structure of parenchyma of lung; Technology; Time; Tissues; Validation; advanced disease; biomarker panel; cancer cell; cancer invasiveness; cell mediated immune response; clinical development; exome sequencing; indexing; lung cancer screening; lung carcinogenesis; multidisciplinary; multiple omics; neoantigens; neoplastic cell; novel; pre-clinical; pressure; prevent; prospective; single cell technology; temporal measurement; transcriptome sequencing; tumor growth; tumor microenvironment; tumorigenesis

ABSTRACT The Characterization Unit seeks a comprehensive understanding of molecular, cellular, and tissue changes that drive lung cancer development and progression during its very earliest stages. Lung cancer tumorigenesis occurs long before the development of clinically apparent disease, which affords the opportunity for intervention in this extended preclinical phase. Our multidisciplinary team will utilize state-of-the-art multi-omic technologies to address the key determinants that cause a pulmonary premalignant lesion (PML) to progress to invasive malignancy. In this first aim, we will utilize established assays to evaluate molecular and cellular alterations that contribute to lung carcinogenesis and pilot technologies in retrospective cohorts of lung premalignancy. Here we will address the evolution of premalignancy in the context of established cancers in cross-sectional analysis of both lung squamous (LUSC) and adenocarcinoma (LUAD) that have been previously banked from surgical specimens. The paramount challenge of delineating the determinants of progression or regression will be addressed in Aim 2 utilizing the molecular and cellular phenotyping of lung PMLs by employing established assays, and incorporating emerging higher resolution (single cell) technologies and successful pilot assays from Aim 1 in prospective cohorts. Here longitudinal prospective studies will allow temporal and spatial analysis of premalignancy. Precise clinical annotation will facilitate determination of critical translational outcomes. Because the premalignant microenvironment (PME) may either promote or constrain the development of invasive lung cancer, the Characterization Unit will evaluate the PME through extensive immune profiling. This investigation will facilitate subsequent analysis of the interplay between mutational load and gene expression status of premalignant cells and immune recognition, including identification of neoantigens and immunoediting, throughout the evolution of premalignancy. Using biospecimens procured by the Biospecimen Unit, the Characterization Unit will utilize technologies that yield multidimensional, large-scale data that can be analyzed by the Data Analysis Unit to discover relationships associated with disease progression. Technology platforms to be utilized to assess lung premalignancy and the corresponding microenvironment include: whole tissue (bulk) and single cell DNA- and RNA-sequencing, single nuclei RNA- sequencing, RNA in situ (SNAIL), highly multiplexed (40–50 markers/panel) imaging technologies including multiplexed ion beam imaging (MIBI), and CO-Detection by indEXing (CODEX) (including with Ce3D technology) in addition to validation by multiplex immunofluorescence (MIF). This Unit will ultimately provide the data that informs our understanding of the pathogenesis of lung cancer from its earliest appearance as premalignancy to invasive disease. This research will afford the opportunity to shift the paradigm from advanced disease intervention to early interception that prevents the progression of pulmonary premalignancy.

抽象的 表征单元寻求对分子、细胞和组织变化的全面了解 在肺癌的最早阶段推动肺癌的发展和进展。 早在临床上明显的疾病发生之前就发生了，这为 我们的多学科团队将利用最先进的多组学技术来干预这一扩展的临床前阶段。 解决导致肺部癌前病变 (PML) 进展的关键决定因素的技术 在第一个目标中，我们将利用现有的检测方法来评估分子和细胞。 导致肺癌发生的改变和回顾性肺癌队列中的试点技术 在这里，我们将讨论癌症前期的演变。 肺鳞癌（LUSC）和腺癌（LUAD）的横断面分析 以前从手术标本中提取的最大挑战是描述其决定因素。 回归或回归将在目标进展 2 中利用肺的分子和细胞表型来解决 通过采用已建立的检测方法并结合新兴的更高分辨率（单细胞）技术来实现 PML 目标 1 在前瞻性队列中的成功试点试验将允许进行前瞻性纵向研究。 癌前病变的时间和空间分析将有助于关键的确定。 因为癌前微环境（PME）可能会促进或限制转化结果。 随着浸润性肺癌的发展，表征单元将通过广泛的评估 PME 这项研究将有助于随后分析突变负荷之间的相互作用。 癌前细胞的基因表达状态和免疫识别，包括识别 新抗原和免疫编辑，在整个癌前病变的演变过程中使用通过获得的生物样本。 生物样本单元、表征单元将利用产生多维、大规模的技术 数据分析单元可以分析数据之间的关系，以发现与疾病相关的数据 用于评估肺部癌前病变和相应进展的技术平台。 微环境包括：整个组织（大量）和单细胞 DNA 和 RNA 测序、单核 RNA 测序 测序、RNA 原位 (SNAIL)、高度多重（40-50 个标记/组）成像技术，包括 多重离子束成像 (MIBI) 和索引共检测 (CODEX)（包括使用 Ce3D 技术）以及多重免疫荧光（MIF）验证，该单元最终将提供。 这些数据帮助我们了解肺癌从最早出现的发病机制 这项研究将提供从癌前病变到侵袭性疾病的转变的机会。 从先进的疾病干预到早期拦截，防止肺恶性肿瘤进展。