Phenotype Interactions in SCLC Development and Detection

SCLC 发展和检测中的表型相互作用

基本信息

批准号：
9788304
负责人：
Alissa M Weaver
金额：
$ 30.6万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788304
关键词：
ASCL1 gene Affect Automobile Driving Biological Assay Biology Biopsy Specimen CD44 gene Cell Communication Cell Line Cell Survival Cells Chromatin Clinical Markers Collection Computerized Medical Record DNA DNA Sequence Alteration Data Detection Development Diagnostic radiologic examination Disease Disease susceptibility Dissection Early Diagnosis Ecosystem Epithelial Cells Event Evolution Genes Genetic Genetically Engineered Mouse Germ-Line Mutation Goals Growth Growth and Development function Heterogeneity Human In Vitro Intervention Lead Link Lung MAP Kinase Gene MYC Gene Amplification Maintenance Malignant Epithelial Cell Malignant neoplasm of lung Mesenchymal Methods Microscope Molecular Mus Mutation Neoplasm Metastasis Neuroendocrine Cell Neuroendocrine Tumors Neurosecretory Systems PTEN gene Patients Phenotype Plasma Plasma Proteins Population Predisposition Prevention Proteins RB1 gene Recurrence Risk Marker Role Sampling Smoking Source Supporting Cell TP53 gene Testing Transplantation Treatment outcome Tumor-Derived Work base biomarker validation cancer stem cell cell free DNA cell growth cell type clinically relevant early detection biomarkers exosome experimental study extracellular vesicles follow-up human data in vivo lung small cell carcinoma macrophage mouse model neoplastic cell notch protein novel novel strategies outcome forecast protein biomarkers release factor self-renewal single-cell RNA sequencing tumor tumor growth tumor heterogeneity tumor initiation tumor microenvironment tumor progression tumorigenesis tumorigenic virtual

项目摘要

PROJECT SUMMARY Small Cell Lung Carcinoma (SCLC) is an aggressive neuroendocrine subtype of lung cancer. SCLC patients have a very low 5-year survival, in part because SCLC tumors are often detected at a late stage when the tumors have already metastasized and treatment outcomes are worse. Thus, early detection becomes critical to achieve better treatment results. Emerging evidence supports the idea that, while SCLC tumors seem homogeneous when examined under a microscope, these tumors contain a significant level of intra-tumoral heterogeneity. Indeed, recent observations by our group and others have identified distinct cellular phenotypes in SCLC, including in primary human tumors, in cell lines derived from human tumors, and in tumors from genetically-engineered mouse models. Importantly, data from our group indicate that these cellular phenotypes contribute to SCLC development. The specific goal of this proposal is to elucidate how different cellular subpopulations within SCLC tumors drive early SCLC development, dynamics, and growth and to leverage this mechanistic information to identify biomarkers for early detection and prevention of SCLC. We have previously identified tumor-propagating cells (TPCs) in SCLC tumors and found that these cells are neuroendocrine and strongly tumorigenic. We have also characterized cell populations derived from these TPCs with distinct phenotypes, including non-neuroendocrine NOTCH+ and CD44+ subpopulations, that promote the growth and survival of the neuroendocrine TPCs. Leveraging these findings as well as our unique genetic mouse models that allow dissection of SCLC phenotype evolution, we will investigate how cell-cell interactions of these distinct SCLC cell phenotypes contribute to tumor development and growth, in relationship with the tumor microenvironment. We will also elucidate the role of secretory factors released by these SCLC subpopulations in driving survival, growth, and phenotype composition of SCLC tumors. Finally, we will perform analysis of cfDNA and proteins (including on exosomes) present in SCLC patient plasma for identification of related markers of SCLC development and early detection. We will also follow up on intriguing findings that germline mutations in NOTCH are present in a large fraction of SCLC patients, suggesting a potential risk marker beyond smoking. This interdisciplinary basic-translational project will elucidate fundamental mechanisms of SCLC development and may lead to novel methods for early detection and/or prevention of SCLC.

项目摘要小细胞肺癌（SCLC）是肺癌的侵略性神经内分泌亚型。 SCLC 患者的5年生存率非常低，部分是因为经常在晚期检测到SCLC肿瘤肿瘤已经转移，治疗结果恶化。因此，早期发现变为对于获得更好的治疗结果至关重要。新兴证据支持以下观点，尽管SCLC肿瘤似乎在显微镜下检查同质时，这些肿瘤含有明显水平的肿瘤内异质性。实际上，我们小组和其他人的最新观察发现了不同的细胞表型在SCLC中，包括原发性肿瘤，在源自人类肿瘤的细胞系中以及来自遗传工程的小鼠模型。重要的是，来自我们组的数据表明这些细胞表型有助于SCLC开发。该提案的具体目标是阐明如何不同的蜂窝 SCLC肿瘤内的亚群推动了SCLC的早期发展，动态和增长，并利用这一点机械信息以识别生物标志物以早期检测和预防SCLC。我们先前已经鉴定出SCLC肿瘤中的肿瘤传播细胞（TPC），发现这些细胞是神经内分泌和强烈肿瘤的。我们还表征了这些细胞种群具有不同表型的TPC，包括非白云母内分泌notch+和CD44+亚群促进神经内分泌TPC的生长和生存。利用这些发现以及我们的独特允许解剖SCLC表型演化的遗传小鼠模型，我们将研究细胞细胞这些独特的SCLC细胞表型的相互作用有助于肿瘤的发展和生长与肿瘤微环境。我们还将阐明这些SCLC释放的分泌因素的作用 SCLC肿瘤的生存，生长和表型组成中的亚群。最后，我们会的对SCLC患者血浆中存在的CFDNA和蛋白质（包括外泌体）进行分析 SCLC开发和早期检测的相关标记鉴定。我们还将跟进有趣的发现Notch中的种系突变存在于大量SCLC患者中，这表明潜在的风险标记超出吸烟。这个跨学科的基本翻译项目将阐明SCLC的基本机制开发并可能导致新的早期检测和/或预防SCLC的方法。