Molecular and cellular mechanisms of SCLC metastasis

SCLC转移的分子和细胞机制

• 批准号: 9353182
• 负责人: JULIEN SAGE
• 金额: $ 44.19万
• 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: 2016-05-20 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353182
• 关键词: Automobile Driving; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biology; Blocking Antibodies; Cancer Biology; Cancer Patient; Cancer cell line; Cell Count; Cell Culture Techniques; Cell Surface Proteins; Cell surface; Cells; Chromatin; Clinic; Clinical; Complex; Coupled; Data; Data Set; Development; Disease; Disseminated Malignant Neoplasm; Distant; Enhancers; Family; Gene Expression; Gene Expression Alteration; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomic Segment; Genomic approach; Genomics; Goals; Growth; Health; Human; In Vitro; Intravenous; Liver; Malignant Neoplasms; Malignant neoplasm of lung; Methodology; Methods; Molecular; Mus; NFIB gene; Neoplasm Metastasis; Neuraxis; Neuroendocrine Tumors; Neurons; Neurosecretory Systems; Organ; Patients; Phenotype; Population; Positioning Attribute; Primary Neoplasm; Role; S-Phase Fraction; Series; Signal Pathway; Smoker; Specimen; Survival Rate; Testing; Tissue Sample; Transplantation; Up-Regulation; Variant; axon growth; base; cancer cell; experimental study; gene function; genome-wide; human tissue; in vitro Assay; in vivo; innovation; insight; killings; loss of function; lung small cell carcinoma; metastatic process; mouse model; multiple sclerosis patient; neoplastic cell; novel; novel therapeutic intervention; pre-clinical; prevent; programs; public health relevance; receptor; relating to nervous system; targeted treatment; transcription factor; tumor; tumor progression; virtual

 DESCRIPTION (provided by applicant): Small Cell Lung Cancer (SCLC) is a neuroendocrine subtype of lung cancer. SCLC tumors have unique biology, with a high proliferative index and aggressive metastatic potential. Treatment options for SCLC have remained virtually unchanged for the past 30 years, with corresponding little improvement in survival rates. The world's population continues to increase and the number of smokers still 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. We aim to develop an understanding of the molecular and cellular mechanisms underlying SCLC progression to aid in the identification of novel therapeutic approaches. Here we specifically propose to investigate the mechanisms driving the metastatic spread of SCLC. Given the lack of human specimens for metastatic SCLC, we have developed a genetically engineered mouse model of SCLC in which we can isolate pure populations of cancer cells from primary tumors and metastases. Using this murine model and novel genomic methodologies, we identified genome-wide transcriptional and chromatin changes in metastatic SCLC cells. These unbiased approaches uncovered several candidate regulators of the metastatic process in SCLC. In particular, we found increased expression of the NFIB transcription factor in metastatic SCLC cells, which correlates with a stabilization of open chromatin at a very large number of enhancer regions containing NFIB binding sites across the genome. Based on these observations, we hypothesize that increased levels of NFIB drive chromatin and transcriptional changes that promote metastasis in SCLC cells. Our first goal is to determine the specific stage(s) of the metastatic cascade at which NFIB may act. To this end, we will perform a series of experiments in culture and in mice. Our second goal is to conduct additional unbiased genomic analyses to define: (i) the gene programs regulated by NFIB, (ii) the molecular mechanisms by which NFIB drives the increased accessibility of a genomic regions and (iii) how NFIB induces gene expression programs that promote metastatic ability. In particular, we will investigate transcription factors involved in th biology of neural cells that may act as co-factors with NFIB to promote SCLC metastasis. Finally, we will examine the role of the NFIB target and neuronal cell surface molecule Lingo1 in SCLC metastasis. These experiments will include pre-clinical assays blocking Lingo1 to determine if Lingo1 may become a clinical target to prevent the metastatic spread of SCLC cells in patients. These experiments will provide novel insights into the basic mechanisms of metastatic progression and identify innovative strategies for targeted therapy for 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肿瘤具有独特的生物学特性，具有高增殖指数和侵袭性转移潜力。在过去的30年里，SCLC的治疗选择几乎没有变化，相应的生存率几乎没有提高。世界人口继续增加，吸烟者的人数也随之增加。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。我们的目标是发展的分子和细胞机制的理解SCLC的进展，以帮助识别新的治疗方法。在这里，我们特别提出调查的机制，推动转移扩散的小细胞肺癌。由于缺乏转移性SCLC的人类样本，我们已经开发了一种基因工程改造的SCLC小鼠模型，其中我们可以从原发性肿瘤和转移瘤中分离出纯的癌细胞群。使用这种小鼠模型和新的基因组方法，我们确定了转移性SCLC细胞的全基因组转录和染色质变化。这些无偏倚的方法揭示了SCLC转移过程的几个候选调节因子。特别是，我们发现转移性SCLC细胞中NFIB转录因子的表达增加，这与基因组中含有NFIB结合位点的大量增强子区域处的开放染色质的稳定化相关。基于这些观察，我们假设NFIB水平的增加驱动染色质和转录变化，促进SCLC细胞的转移。我们的第一个目标是确定NFIB在转移级联反应中的具体阶段， 可以采取行动。为此，我们将在培养物和小鼠中进行一系列实验。我们的第二个目标是进行额外的无偏基因组分析，以确定：（i）由NFIB调节的基因程序，（ii）NFIB驱动基因组区域可及性增加的分子机制，以及（iii）NFIB如何诱导促进转移能力的基因表达程序。特别是，我们将研究参与神经细胞生物学的转录因子，这些转录因子可能作为NFIB的辅助因子促进SCLC转移。最后，我们将研究NFIB靶点和神经元细胞表面分子Lingo 1在小细胞肺癌转移中的作用。这些实验将包括阻断Lingo 1的临床前试验，以确定Lingo 1是否可能成为预防患者SCLC细胞转移扩散的临床靶点。这些实验将为转移进展的基本机制提供新的见解，并为SCLC（最致命的肺癌形式）的靶向治疗确定创新策略。