Molecular and cellular mechanisms of SCLC metastasis

 描述(申请人提供)：小细胞肺癌(SCLC)是肺癌的一种神经内分泌亚型。小细胞肺癌具有独特的生物学特性，具有较高的增殖指数和侵袭性转移潜能。在过去的30年里，小细胞肺癌的治疗选择几乎没有变化，相应地，存活率几乎没有改善。世界人口继续增加，吸烟者的数量仍然紧随其后。因此，每年导致20多万名患者死亡的小细胞肺癌--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。我们的目标是了解小细胞肺癌进展的分子和细胞机制，以帮助识别新的治疗方法。在这里，我们特别建议研究小细胞肺癌转移扩散的机制。鉴于缺乏转移性小细胞肺癌的人类标本，我们开发了一种小鼠基因工程模型，在该模型中，我们可以从原发肿瘤和转移瘤中分离出纯净的癌细胞群体。利用这个小鼠模型和新的基因组方法，我们确定了转移性小细胞肺癌细胞全基因组转录和染色质的变化。这些不偏不倚的方法揭示了小细胞肺癌转移过程的几个候选调节因子。特别是，我们发现在转移的SCLC细胞中NFIB转录因子的表达增加，这与基因组中包含NFIB结合位点的大量增强子区域的开放染色质的稳定有关。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，从而促进SCLC细胞的转移。我们的第一个目标是确定NFIB转移级联的特定阶段(S) 可能会采取行动。为此，我们将在培养和小鼠身上进行一系列实验。我们的第二个目标是进行更多的无偏见的基因组分析，以确定：(I)受NFIB调控的基因程序，(Ii)NFIB驱动基因组区域可访问性增加的分子机制，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促进小细胞肺癌转移的辅助因子。最后，我们将研究NFIB靶标和神经细胞表面分子Lingo1在小细胞肺癌转移中的作用。这些实验将包括阻断Lingo1的临床前试验，以确定Lingo1是否可能成为防止SCLC细胞在患者体内转移的临床靶点。这些实验将为转移进展的基本机制提供新的见解，并确定针对小细胞肺癌--最致命的肺癌--的靶向治疗的创新策略。

 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.