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(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

基本信息

批准号：
9379312
负责人：
Moumita Ghosh
金额：
$ 44.26万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9379312
关键词：
Address Biopsy Bronchoscopy Cancer Etiology Carcinoma Cell physiology Cells Chemoprevention Chemopreventive Agent Cytometry DNA Sequence Alteration Data Development Dysplasia Elements Endothelial Cells Epigenetic Process Epithelial Epithelium Event Evolution Exhibits FGFR1 gene Functional disorder Future Genomics Goals Heterogeneity Histologic Iloprost Immune In Vitro Incidence Inflammation Intervention Lesion Maintenance Malignant Neoplasms Malignant neoplasm of lung Measures Methylation Molecular Mutate Mutation Neoplasms Pathway interactions Patient risk Patients Premalignant Preventive Property Recording of previous events Risk Site Smoker Somatic Mutation Squamous Cell Lung Carcinoma Stem cells Stromal Cells TP53 gene Testing Time Work angiogenesis base cancer invasiveness cancer site carcinogenesis carcinogenicity cell type design exome genetic profiling genomic profiles high risk immune checkpoint improved outcome lung development migration mortality novel novel chemoprevention novel therapeutics predictive marker prevent progenitor public health relevance repaired response secondary analysis self-renewal smoking cessation transcriptome sequencing transcriptomics tumor

项目摘要

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.

项目总结/文摘