Molecular and cellular mechanisms of SCLC metastasis

点击翻译按钮获取中文摘要

 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.