Notch signaling in small cell lung carcinoma

小细胞肺癌中的Notch信号传导

• 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
• 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

 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（由申请人提供）：小细胞肺癌（SCLC）是肺癌的神经内分泌亚型。SCLC患者的5年生存率令人沮丧，这在很大程度上是由于化疗的非常短暂的影响和缺乏针对这种癌症类型的靶向治疗。世界人口持续增加，吸烟者的数量也随之迅速增加。因此，每年导致20多万患者死亡的小细胞肺癌--其中大多数是重度吸烟者--将在未来几十年继续成为一个主要的健康问题。我们的总体目标是更好地了解SCLC发展的机制，以帮助未来开发新的治疗策略。Notch信号传导控制多个谱系中的细胞命运和分化。有趣的是，Notch途径也涉及各种癌症类型，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。然而，Notch信号传导的作用是上下文依赖性的，在不同的细胞谱系中充当癌基因或肿瘤抑制因子。因此，彻底研究Notch途径在肿瘤细胞中的作用模式至关重要。 在任何临床策略可以安全地实施之前的特定背景下。越来越多的证据表明，Notch信号通路在小细胞肺癌中可能发挥抑瘤作用。在某种程度上，这些作用可能是由于Notch抑制神经内分泌分化，类似于肺发育期间和成年肺上皮对损伤的反应。然而，Notch途径在SCLC发展和对治疗的反应中的确切作用尚未确定。我们将使用小鼠遗传学，原代小鼠和人类癌细胞，以及分子，生物化学和基因组学工具的组合来解决这些关键问题。具体而言，我们已经做出了有趣的观察，即Notch通路活性肿瘤细胞的一部分天然存在于SCLC肿瘤中，定义了SCLC中肿瘤异质性的新水平。我们将研究这些Notch通路活性肿瘤细胞如何与肿瘤的其余部分相互作用，包括这些细胞可能的肿瘤促进作用。我们还发现，所有肿瘤细胞中Notch的异位激活最初抑制SCLC的生长，但在第二阶段，将SCLC神经内分泌肿瘤细胞重编程为非神经内分泌状态，其中Notch成为致癌的。在这些数据的基础上，我们将确定Notch激活抑制SCLC细胞而不触发这种抑制的最佳条件。 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细胞重编程为非神经内分泌命运的分子机制。这些实验将为Notch信号传导的基本机制提供新的见解，并可能有助于确定针对SCLC（最致命的肺癌形式）的靶向治疗的新策略。