Phenotype Interactions in SCLC Development and Detection

SCLC 发展和检测中的表型相互作用

• 批准号: 10246932
• 负责人: Alissa M Weaver
• 金额: $ 31.55万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246932
• 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; Prognosis; 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; protein biomarkers; release factor; self-renewal; single-cell RNA sequencing; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic; virtual

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.

项目概要 小细胞肺癌（SCLC）是肺癌的一种侵袭性神经内分泌亚型。小细胞肺癌 患者的 5 年生存率非常低，部分原因是 SCLC 肿瘤通常在晚期才被发现。 肿瘤已经转移，治疗效果更差。因此，早期检测就变成了 对于获得更好的治疗效果至关重要。新出现的证据支持这样的观点：虽然 SCLC 肿瘤似乎 当在显微镜下检查时，这些肿瘤是均匀的，含有显着水平的瘤内 异质性。事实上，我们小组和其他人最近的观察发现了不同的细胞表型 在 SCLC 中，包括原发性人类肿瘤、源自人类肿瘤的细胞系以及来自 基因工程小鼠模型。重要的是，我们小组的数据表明这些细胞表型 为SCLC的发展做出贡献。该提案的具体目标是阐明不同的细胞如何 SCLC 肿瘤内的亚群驱动早期 SCLC 的发展、动态和生长，并利用这一点 识别生物标志物的机制信息，用于早期检测和预防 SCLC。 我们之前已经在 SCLC 肿瘤中鉴定出肿瘤增殖细胞 (TPC)，并发现这些细胞 具有神经内分泌性和强致瘤性。我们还对源自这些的细胞群进行了表征 具有不同表型的 TPC，包括非神经内分泌 NOTCH+ 和 CD44+ 亚群， 促进神经内分泌 TPC 的生长和存活。利用这些发现以及我们独特的 允许剖析 SCLC 表型进化的遗传小鼠模型，我们将研究细胞-细胞如何 这些不同的 SCLC 细胞表型之间的相互作用有助于肿瘤的发展和生长， 与肿瘤微环境有关。我们还将阐明这些 SCLC 释放的分泌因子的作用 驱动 SCLC 肿瘤存活、生长和表型组成的亚群。最后，我们将 对 SCLC 患者血浆中存在的 cfDNA 和蛋白质（包括外泌体）进行分析 鉴定 SCLC 发展和早期检测的相关标志物。我们也会跟进一些有趣的事情 研究结果表明，NOTCH 种系突变存在于大部分 SCLC 患者中，这表明 吸烟以外的潜在风险标志。 这个跨学科的基础转化项目将阐明 SCLC 的基本机制 的发展，并可能带来早期检测和/或预防 SCLC 的新方法。