Novel Mechanisms Controlling SCLC Tumor Initiation

项目概要/摘要 本项目的目的是鉴定小细胞肺癌（SCLC）的新分子决定因素 癌前发育相对而言，人们对引发这种疾病的分子机制知之甚少。 这种高度侵袭性、广泛转移性和致命性肺癌的癌前病变。几乎所有SCLC患者 是，或者曾经是，重度吸烟者。编码肿瘤抑制因子TP 53和TP 54的基因中的功能缺失突变 Rb 1几乎存在于所有的SCLC肿瘤中。此外，TP 53和Rb 1最近已被证明可以限制 肺神经内分泌细胞（PNEC）的自我更新，PNEC是SCLC的起源细胞。尽管 这些和其他对SCLC分子发病机制至关重要的遗传改变的记录， 有效治疗靶点的鉴定受到限制。检测SCLC特有的关键漏洞 将是消除肺癌死亡的一个重大进步。一个潜在的贡献者， 导致SCLC发展的癌前病变是Ras 2的分子支架激酶抑制剂（KSR 2）。我们 分析表明，分子支架KSR 2在正常肺组织中是检测不到的，但在正常肺组织中是稳健的。 在PNEC和SCLC细胞系中表达，主要是那些最常见的Achaete-scute复合体 同源物1（ASCL 1）亚型。这种相关性的发展和进展的相关性， 先前的观察结果暗示了肿瘤前SCLC病变，（1）ChIP-seq分析显示KSR 2是一种肿瘤前病变， ASCL 1在SCLC中的转录靶点，以及（2）ASCL 1对于正常肺的发育是必需的 神经内分泌细胞和SCLC内的肿瘤起始能力。类似地，KSR 2敲除显著地 在体外和体内抑制高度致瘤性SCLC亚群的克隆形成和自我更新。 这些数据表明，KSR 2是必不可少的自我更新和长期传播的假设， 对SCLC形成至关重要的基础神经内分泌群体，将通过1）确定 KSR 2在PNEC和SCLC TPC自我更新和SCLC肿瘤形成中的作用，以及2）定义KSR 2- 介导的信号通路，支持SCLC TPC自我更新。

PROJECT SUMMARY / ABSTRACT The goal of this project is to identify novel molecular determinants of small-cell lung carcinoma (SCLC) preneoplastic development. Relatively little is known about the molecular mechanisms that initiate preneoplasia in this highly aggressive, widely metastatic, and lethal lung cancer. Almost all patients with SCLC are, or were, heavy smokers. Loss-of-function mutations in genes encoding the tumor suppressors TP53 and Rb1 occur in almost all SCLC tumors. Moreover, TP53 and Rb1 have been shown recently to constrain the self-renewal of pulmonary neuroendocrine cells (PNECs), which are a cell of origin for SCLC. Despite the documentation of these and other genetic alterations essential to the molecular pathogenesis of SCLC, the identification of effective therapeutic targets has been limited. Detection of key vulnerabilities unique to SCLC would be a major advance toward eradicating deaths from lung cancer. One potential contributor to the preneoplastic leading to SCLC development is the molecular scaffold Kinase Suppressor of Ras 2 (KSR2). Our analysis reveals that the molecular scaffold KSR2 is undetectable in normal lung tissue but is robustly expressed in PNECs and SCLC cell lines, predominantly those of the most common Achaete-scute complex homolog 1 (ASCL1) subtype. The relevance of this correlation to the development and progression of preneoplastic SCLC lesions is implied by previous observations that (1) ChIP-seq analysis revealed KSR2 as a transcriptional target of ASCL1 in SCLC, and (2) that ASCL1 is essential for the development of normal lung neuroendocrine cells and for the tumor-initiating capacity within SCLC. Similarly, KSR2 knockdown markedly suppresses clonogenicity and self-renewal in highly tumorigenic SCLC subpopulations in vitro and in vivo. These data suggest the hypothesis that KSR2 is essential for self-renewal and long-term propagation of a foundational neuroendocrine population essential to SCLC formation, which will be tested by 1) determining the role of KSR2 in PNEC and SCLC TPC self-renewal and SCLC tumor formation and 2) defining the KSR2- mediated signaling pathways that support SCLC TPC self-renewal.