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。过去 30 年来，SCLC 的治疗方案几乎没有变化，相应的生存率也几乎没有改善。世界人口持续增加，吸烟者数量也随之增加。因此，每年导致超过 200,000 名患者死亡的 SCLC（其中大多数是重度吸烟者）在未来几十年仍将是一个主要的健康问题。我们的目标是加深对 SCLC 进展的分子和细胞机制的了解，以帮助确定新的治疗方法。在这里，我们特别建议研究驱动 SCLC 转移扩散的机制。鉴于缺乏转移性 SCLC 的人类标本，我们开发了一种 SCLC 基因工程小鼠模型，在该模型中我们可以从原发性肿瘤和转移瘤中分离出纯癌细胞群。利用这种小鼠模型和新颖的基因组方法，我们确定了转移性 SCLC 细胞的全基因组转录和染色质变化。这些公正的方法发现了 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，这与基因组中大量含有 NFIB 结合位点的增强子区域开放染色质的稳定相关。基于这些观察结果，我们假设 NFIB 水平升高会驱动染色质和转录变化，从而促进 SCLC 细胞的转移。我们的首要目标是确定 NFIB 发生转移级联的具体阶段 可能会行动。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公正基因组分析，以确定：(i) 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，我们将研究神经细胞生物学中涉及的转录因子，这些转录因子可能作为 NFIB 的辅助因子来促进 SCLC 转移。最后，我们将研究 NFIB 靶点和神经元细胞表面分子 Lingo1 在 SCLC 转移中的作用。这些实验将包括阻断 Lingo1 的临床前测定，以确定 Lingo1 是否可以成为预防患者 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，并确定 SCLC（最致命的肺癌形式）靶向治疗的创新策略。