Novel Mechanisms Controlling SCLC Tumor Initiation

项目摘要/摘要 本项目的目标是确定小细胞肺癌(SCLC)的新分子决定因素。 癌前发育。人们对其启动的分子机制知之甚少。 这是一种高度侵袭性、广泛转移和致命性的肺癌。几乎所有的小细胞肺癌患者 现在是，或者曾经是烟瘾很大的人。编码肿瘤抑制基因TP53和TP53的功能丧失突变 Rb1几乎存在于所有的小细胞肺癌肿瘤中。此外，TP53和Rb1最近被证明可以限制 肺神经内分泌细胞(PNECs)的自我更新，它是小细胞肺癌的起源细胞。尽管 记录这些和其他对小细胞肺癌分子发病机制至关重要的基因改变， 有效治疗靶点的确定一直受到限制。检测SCLC特有的关键漏洞 将是在根除肺癌死亡方面的重大进步。一位潜在的贡献者 导致小细胞肺癌发生的癌前病变是RAS-2的分子支架激酶抑制因子(KSR2)。我们的 分析表明，KSR2分子支架在正常肺组织中检测不到，但很健壮 在PNECs和SCLC细胞系中表达，主要是那些最常见的Achaete-scute复合体 同源基因1(ASCL1)亚型。这种相关性与疾病的发展和进展的相关性 先前的观察提示：(1)CHIP-SEQ分析显示KSR2是一种 ASCL1在小细胞肺癌中的转录靶点；(2)ASCL1对正常肺的发育是必不可少的 神经内分泌细胞和小细胞肺癌内肿瘤的启动能力。同样，KSR2基因显著下调 在体外和体内抑制高致瘤性小细胞肺癌亚群的克隆性和自我更新。 这些数据表明，假设KSR2是自我更新和长期繁殖的关键 对小细胞肺癌形成至关重要的基础神经内分泌种群，将通过1)确定 KSR2在PNEC和SCLC、TPC自我更新和SCLC肿瘤形成中的作用；2)定义KSR2- 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.