Notch signaling in small cell lung carcinoma

小细胞肺癌中的Notch信号传导

基本信息

批准号：
9122074
负责人：
JULIEN SAGE
金额：
$ 37.1万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122074
关键词：
Address Adult Biochemical Cancer Etiology Cancer cell line Cell Cycle Progression Cell Fate Control Cell Lineage Cells Cessation of life Chromatin Clinical Data Development Disease Early Diagnosis Epithelium Future Gene Expression Genes Genetic Genetically Engineered Mouse Genomic approach Goals Growth Health Heterogeneity Human Investigation Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Methodology Modeling Molecular Mus Neuroendocrine Tumors Neuroglia Neurosecretory Systems Non-Small-Cell Lung Carcinoma Notch Signaling Pathway Oncogenes Oncogenic Pathway interactions Patients Phase Play Population Primary Neoplasm Regimen Rest Role Signal Pathway Signal Transduction Smoker Stress Testing Therapeutic Transcription Repressor/Corepressor Tumor Suppressor Proteins Work base cancer cell cancer type chemotherapy curative treatments genomic tools insight killings lung development lung small cell carcinoma mouse model neoplastic cell new therapeutic target notch protein novel novel strategies novel therapeutics public health relevance relating to nervous system research study response response to injury screening small hairpin RNA targeted treatment tool transcriptome sequencing treatment response tumor tumor heterogeneity

项目摘要

DESCRIPTION (provided by applicant): Small Cell Lung Carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. The 5-year survival of SCLC patients is dismal, in large part due to the very transient effects of chemotherapy and the absence of targeted therapies against this cancer type. The world's population continues to increase and the number of smokers quickly follows. Thus, SCLC, which kills more than 200,000 patients every year - most of them heavy smokers - will continue to be a major health issue in the decades to come. Our overarching goal is to gain a better understanding of the mechanisms underlying SCLC development to aid in the development of novel therapeutic strategies in the future. Notch signaling controls cell fate and differentiation in multiple lineages. Interestingly, the Notch pathway is also implicated in various cancer types, and an increasing number of therapeutic tools are being developed to target this pathway in tumor cells. However, the role of Notch signaling is context-dependent, acting as an oncogene or a tumor suppressor in different cell lineages. Thus, it is critical to thoroughly investigate the mode of action of the Notch pathway in specific contexts before any clinical strategy may be safely implemented. Accumulating evidence suggests that active Notch signaling may play a tumor suppressive role in SCLC. In part, these effects may be due to the inhibition of neuroendocrine differentiation by Notch, similar to what is seen during lung development and in the adult lung epithelium in response to injury. However, the exact role of the Notch pathway in SCLC development and response to therapy has not been determined. We will use a combination of mouse genetics, primary mouse and human cancer cells, and molecular, biochemical, and genomics tools to address these key questions. Specifically, we have made the intriguing observation that a contingent of Notch pathway-active tumor cells is naturally present in SCLC tumors, defining a new level of tumor heterogeneity in SCLC. We will investigate how these Notch pathway-active tumor cells interact with the rest of the tumor, including possible tumor-promoting roles for these cells. We have also found that ectopic activation of Notch in all tumor cells initially suppresses the growth of SCLC but, in a second phase, reprograms SCLC neuroendocrine tumor cells towards a non-neuroendocrine state in which Notch becomes oncogenic. Building upon these data, we will determine the optimal conditions for Notch activation to inhibit SCLC cells without triggering this oncogenic switch. Finally, we will use advanced molecular and genomic tools to elucidate the molecular mechanisms by which Notch activation reprograms SCLC cells to a non-neuroendocrine fate. These experiments will provide novel insights into the basic mechanisms of Notch signaling and may help identify novel strategies for targeted therapy directed at SCLC, the most lethal form of lung cancer.

描述（由适用提供）：小细胞肺癌（SCLC）是肺癌的神经内分泌亚型。 SCLC患者的5年生存期令人沮丧，这在很大程度上是由于化学疗法的短暂作用以及针对这种癌症类型的靶向疗法的短暂作用。世界人口继续增加，吸烟者的数量很快随之而来。这是SCLC每年杀死200,000多名患者（其中大多数吸烟者）将继续成为未来几十年的重大健康问题。我们的总体目标是更好地了解SCLC开发的机制，以帮助未来发展新型治疗策略。 Notch信号传导控制多个谱系中的细胞命运和分化。有趣的是，在各种癌症类型中也暗示了Notch途径，并且正在开发越来越多的治疗工具来靶向肿瘤细胞中的这一途径。但是，Notch信号的作用是上下文依赖性的，在不同细胞谱系中充当癌基因或肿瘤抑制剂。这是至关重要的可以安全地实施任何临床策略之前的具体情况。积累的证据表明，主动缺口信号传导可能在SCLC中起抑制肿瘤的作用。在某种程度上，这些作用可能是由于Notch抑制神经内分泌的抑制作用，类似于肺发育过程中所见的以及在成年肺上皮响应损伤时所见。但是，尚未确定Notch途径在SCLC发展和对治疗反应中的确切作用。我们将使用小鼠遗传学，原代小鼠和人类癌细胞以及分子，生化和基因组学工具的组合来解决这些关键问题。具体而言，我们已经进行了有趣的观察，即SCLC肿瘤中自然存在Notch途径 - 活性肿瘤细胞的一部分，从而定义了SCLC中新的肿瘤异质性水平。我们将研究这些Notch途径活性肿瘤细胞如何与其余肿瘤相互作用，包括这些细胞的可能促进肿瘤作用。我们还发现，所有肿瘤细胞中Notch的生态激活最初都抑制了SCLC的生长，但在第二阶段，将SCLC神经内分泌肿瘤细胞重新编程向非神经内分泌状态，其中Notch变为致癌性。在这些数据的基础上，我们将确定Notch激活抑制SCLC单元的最佳条件，而无需触发这一点致癌开关。最后，我们将使用先进的分子和基因组工具来阐明Notch激活将SCLC细胞重新编程为非白云母内分泌命运的分子机制。这些实验将为Notch信号的基本机制提供新的见解，并可能有助于确定针对SCLC的靶向治疗的新型策略，SCLC是肺癌的最致命形式。