(PQ1) Progenitor cell malfunction, mutations and changes in microenvironment: A dynamic risk spectrum for cancer evolution

(PQ1) 祖细胞功能障碍、突变和微环境变化：癌症进化的动态风险谱

• 批准号: 10251890
• 负责人: Moumita Ghosh
• 金额: $ 50.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251890
• 关键词: Address; Biopsy; Bronchoscopy; Cancer Etiology; Carcinoma; Cells; Chemoprevention; Chemopreventive Agent; Cytometry; DNA Sequence Alteration; Data; Development; Dysplasia; Elements; Endothelial Cells; Epigenetic Process; Epithelial; Event; Evolution; Exhibits; FGFR1 gene; Functional disorder; Future; Genetic; Genomics; Goals; Heterogeneity; High grade dysplasia; Histologic; Iloprost; Immune; In Vitro; Incidence; Inflammation; Intervention; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methylation; Molecular; Mutate; Mutation; Neoplasms; Pathway interactions; Patients; Preventive; Property; Recording of previous events; Risk; Site; Smoker; Somatic Mutation; Squamous Cell Lung Carcinoma; Stromal Cells; TP53 gene; Testing; Time; Work; angiogenesis; base; cancer invasiveness; cancer site; carcinogenesis; carcinogenicity; cell type; design; epithelial stem cell; exome sequencing; former smoker; genomic profiles; high risk; immune checkpoint; improved outcome; lung development; migration; mortality; novel; novel chemoprevention; novel therapeutic intervention; predictive marker; premalignant; prevent; progenitor; public health relevance; repaired; response; secondary analysis; self-renewal; smoking cessation; stem cell function; stem cells; transcriptome sequencing; transcriptomics; tumor

Project Summary/Abstract In this proposal we will address the provocative question (PQ1): “For tumors that arise from a premalignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors? We will focus on squamous cell lung cancer (SCC), a common cause of cancer mortality and a neoplasm for which there is considerable evidence supporting an origin from a premalignant field. We propose to answer this question through a comprehensive strategy that focuses on three critical elements of the premalignant field for SCC of the lung: epithelial progenitor cell function, which is required for repair and maintenance of a healthy epithelium; genomic alterations in premalignant dysplasias; and the composition and function of the microenvironment. We hypothesize that “Evolution of lung cancer from a field of premalignant dysplasia is driven both by intrinsic changes in epithelial progenitor cells as well as changes that occur in the field microenvironment. Thus, therapy could be targeted to rescue functions of epithelial progenitor cells and/or to restore the microenvironment.” We propose three aims to address this hypothesis. Aim 1. Mechanisms of progenitor malfunction to identify new targets for chemoprevention: We will determine whether epithelial progenitor malfunction in terms of self-renewal and multipotentiality varies across a dysplasia spectrum. We will also assess whether progenitor response to the chemopreventive agent iloprost differs across this dysplasia spectrum. RNA sequencing will explore determinants of progenitor dysfunction and response to iloprost, potentially identifying novel interventions and predictive biomarkers. Aim 2. Detecting novel genomic changes to identify new targets for chemoprevention: We will assess whether the genetic and epigenetic profile of dysplasia varies across the above dysplasia spectrum. Brushings collected from the same dysplasia spectrum will be used to identify mutations, epigenetic alterations and transcriptomal changes; all compared to the tumor in those subjects with SCC. Targetable mutations and pathways will be identified. Aim 3. Changes in composition and function of microenvironment to identify new targets for chemoprevention: We will assess whether the microenvironment varies across the above dysplasia spectrum. Mass cytometry will be used to characterize cells that constitute the field microenvironment. We will also explore cellular heterogeneity in the field in a subset of dysplasias with known history of persistence/progression or regression using single cell transcriptomic profiling of flow-sorted epithelial and non-epithelial cells. Identification of intervention targets, such as immune checkpoints, inflammation and angiogenesis will be our goal. We anticipate that our integrative approach will lead to new strategies to prevent the evolution of premalignancy to invasive SCC.

项目摘要/摘要 在此提案中，我们将解决一个挑衅性的问题（PQ1）：“对于由一个肿瘤引起的 预示例性领域，该领域中细胞的特性可用于设计抑制策略 发展未来肿瘤？ 我们将专注于鳞状细胞肺癌（SCC），这是癌症死亡率和A的常见原因 有大量证据支持起源于婚前场的肿瘤。我们建议 通过全面的策略回答这个问题，该策略重点介绍了三个关键要素 肺SCC的前态场：上皮祖细胞功能，这是修复和 维持健康的上皮；前发育不全的基因组改变；和组成 和微环境的功能。我们假设“肺癌从一个领域的进化 前异增生性疾病既由上皮祖细胞的内在变化以及 现场微环境发生的变化。那就是治疗可以针对拯救功能 上皮祖细胞和/或恢复微环境。“我们提出了三个目标，以解决 这个假设。目标1。祖细胞故障的机制确定新目标 化学预防：我们将确定上皮祖细胞是否在自我更新和 多能性在发育不良谱中变化。我们还将评估祖先对 化学预防剂伊洛前列体在这种发育异常方面有所不同。 RNA测序将探索 确定祖细胞功能障碍和对伊洛列伯斯龙的反应，有可能识别新的干预措施和 预测生物标志物。目标2。检测新的基因组变化以识别新目标 化学预防：我们将评估发育不良的遗传和表观遗传特征在整个过程中是否有所不同 上方的发育不良谱。从同一发育不良谱收集的刷子将用于识别 突变，表观遗传改变和转录组变化；与那些受试者的肿瘤相比 SCC。将确定可靶向的突变和途径。目标3。组成和功能的变化 微环境确定化学预防的新目标：我们将评估是否 上述发育不良谱的微环境变化。质量细胞仪将用于表征 构成现场微环境的细胞。我们还将探索A中的细胞异质性 使用单细胞的持久性/进展或回归史的发育不良的子集 流程上皮和非上皮细胞的转录组分析。识别干预目标， 诸如免疫光点，炎症和血管生成将是我们的目标。我们预计我们的 综合方法将导致新的策略，以防止侵入性SCC的前期演变。