Lineage heterogeneity and plasticity in lung cancer

项目摘要 大规模的基因组研究已经发现了许多相关的改变，激活或激活 肺癌中的信号分子，这导致了显着改善患者的结果和我们的 治疗选择尽管基于基因组的精准医学取得了这些进展， 18%的比例仍然不够。这是由于最终出现的阻力和变异， 治疗的反应，很大程度上是由于肺癌的异质性。为了提高精确度和有效性， 通过未来药物的附加特征区分不同肺癌亚组的创新策略 迫切需要发展。我们假设，我们的自然系统，以满足必要的细胞， 构成器官结构，其功能被模仿正常细胞身份的癌症劫持， 他们的生存。我们以前的研究发现，肺癌细胞携带谱系癌基因扩增， 特别是依赖于它们的表达来生存。需要谱系扩增基因的一个子集， 癌症表明癌细胞中存在独特的脆弱性，这些脆弱性可能处于生存的边缘。然而，在这方面， 这些扩增仅代表肺癌的两种主要亚型中的一小部分。因此本 这项研究将集中在发育过程中必不可少的谱系因素，并控制成人的细胞身份， 其余的肺癌亚型。通过对组蛋白标记的全基因组分析，我们确定了“超级- 增强子（SE）的谱系定义转录因子基因。随后的肺部分层聚类 癌症样品鉴定了对肺癌亚群特异的SE。因此，我们的目标是了解 我们的领导候选人定义了目标1中新子集的谱系状态的重要性。我们将测试 亚类特异性的局部染色质结构，然后研究新的谱系转录因子的作用 特别是在肺ADC的两个主要亚组中富集，无论它们是否对维持肺ADC的功能至关重要， 肺癌细胞的细胞状态，并依赖于其生存的承诺谱系。在目标2中， 确定神经转录因子Brn 2在肺鳞状细胞新的“神经”亚型中的作用 与p63（一种关键的鳞状细胞谱系因子）相比，SCC作为Sox 2的合作伙伴， 以前被认为是典型肺SCC中Sox 2的重要合作伙伴。目标3：追求 诱导转分化作为一种治疗策略，我们试图了解谱系转换是如何发生的， 通过确定谱系状态的异质性和动态来确定肿瘤。我们将确定时间的模式 通过剖析在定义的模型中由遗传扰动引起的谱系状态中的种群转移的动力学 单细胞水平的全基因组染色质景观。然后，我们将测试我们的假设， 使用小鼠模型，异质性与肿瘤的可塑性和侵袭性肿瘤行为相关， 人类标本这些结果将作为这些谱系因素如何促进遗传学的原理证明。 肺癌的形成，并导致新的假设，我们如何可以操纵肺癌细胞的身份。

PROJECT SUMMARY Large-scale genomic studies have discovered numerous relevant alterations that activate or inactivate key signaling molecules in lung cancer, which led to significant improvement on patients' outcome and our therapeutic options. Despite these advances in the genome-based precision medicine, the 5-year survival rate of 18% remains less than adequate. This is attributable to eventual emergence of resistance and variability in response to the treatment, largely due to heterogeneity of lung cancers. To improve precision and efficacy, innovative strategies to distinguish different subgroups of lung cancer by additional features for future drug development are desperately needed. We hypothesize that our natural system to populate necessary cells to constitute the organ structure and its function is hijacked by cancer mimicking normal cell identities to maintain their survival. Our previous studies found lung cancer cells harboring amplification of lineage oncogenes are specifically dependent on their expression for survival. The need for lineage amplified genes in a subset of cancers suggests unique vulnerabilities in cancer cells that may be poised at the brink of survival. However, these amplifications represent only a minor subset of the two major subtypes of lung cancers. Therefore, this study will focus on lineage factors essential during the development and control the cell identity in adult, in the remaining subsets of lung cancers. Through genome-wide profiling of a histone mark, we identified `super- enhancers' (SE) on the lineage-defining transcription factor genes. Subsequent hierarchical clustering of lung cancer samples identified SEs specific to subsets of lung cancers. Therefore, we aim to understand the significance of our lead candidates defining the lineage state of the novel subsets in aim 1. We will test the subclass-specific local chromatin structure and then investigate the roles of novel lineage transcription factors specifically enriched in the two major subgroups of lung ADCs, whether they are essential for maintaining the cellular state of lung cancer cells and are dependent on the committed lineage for their survival. In aim 2, to determine the roles of a neural transcription factor Brn2 in a novel `neural' subtype of lung squamous cell cancers (SCC) as a cooperative partner of Sox2, by contrast to p63, a key squamous lineage factor we previously characterized as an important cooperative partner of Sox2 in classic lung SCC. In aim 3, to pursue inducing transdifferentiation as a therapeutic strategy, we seek to understand how lineage switch occurs within a tumor by determining heterogeneity and dynamics of lineage states. We will determine the mode of temporal dynamics of population shifts in lineage states induced by genetic perturbation in defined models via profiling genome-wide chromatin landscapes at a single cell level. We will then test our hypothesis that the degree of heterogeneity correlates with plasticity of the tumor and aggressive tumor behaviors using a mouse model and human specimens. The results will serve as a proof-of-principle how these lineage factors contribute to the formation of lung cancer and lead to new hypotheses how we can manipulate cell identity of lung cancers.