Novel Mechanisms Controlling SCLC Tumor Initiation

控制 SCLC 肿瘤发生的新机制

• 批准号: 10303538
• 负责人: Robert E. Lewis
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303538
• 关键词: Affect; Biological Assay; Calcineurin; Carboplatin; Cell Line; Cells; Cessation of life; ChIP-seq; Cisplatin; Complex; Coupled; Data; Detection; Development; Documentation; Evolution; Foundations; Generations; Genes; Genetic Models; Genetic Transcription; Goals; Homologous Gene; Human; Impairment; In Vitro; Lesion; Lung; MEKs; Malignant Epithelial Cell; Malignant neoplasm of lung; Mediating; Messenger RNA; Molecular; Mus; Mutation; Nature; Neuroendocrine Cell; Neurosecretory Systems; Nivolumab; Other Genetics; Oxygen Consumption; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphotransferases; Population; Pre-Clinical Model; Proteins; Recording of previous events; Regulation; Research; Role; Signal Pathway; Signal Transduction; Smoker; Smoking; Structure of parenchyma of lung; TP53 gene; Testing; Topotecan; Tumor Suppressor Proteins; Xenograft procedure; anti-PD-L1 antibodies; cancer invasiveness; cancer stem cell; energy balance; improved; in vivo; knock-down; loss of function mutation; lung injury; lung small cell carcinoma; novel; novel therapeutic intervention; programmed cell death protein 1; response; scaffold; self-renewal; therapeutic evaluation; therapeutic target; therapeutically effective; tumor; tumor initiation; tumorigenic

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.

项目概要/摘要 该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。对于引发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 现在或曾经是重度吸烟者。编码肿瘤抑制因子 TP53 和 TP53 的基因发生功能丧失突变 Rb1 存在于几乎所有 SCLC 肿瘤中。此外，TP53 和 Rb1 最近已被证明可以限制 肺神经内分泌细胞 (PNEC) 的自我更新，是 SCLC 的起源细胞。尽管 记录这些和其他对于 SCLC 分子发病机制至关重要的基因改变， 有效治疗靶点的识别受到限制。检测 SCLC 特有的关键漏洞 这将是消除肺癌死亡的重大进步。一位潜在的贡献者 导致 SCLC 发展的肿瘤前期是 Ras 2 (KSR2) 的分子支架激酶抑制剂。我们的 分析表明，分子支架 KSR2 在正常肺组织中检测不到，但稳定存在 在 PNEC 和 SCLC 细胞系中表达，主要是最常见的 Achaete-scute 复合体细胞系 同源物 1 (ASCL1) 亚型。这种相关性与发展和进展的相关性 之前的观察结果暗示了癌前 SCLC 病变：(1) ChIP-seq 分析显示 KSR2 作为一种 SCLC 中 ASCL1 的转录靶标，以及 (2) ASCL1 对于正常肺的发育至关重要 神经内分泌细胞和 SCLC 内的肿瘤启动能力。同样，KSR2 敲低显着 在体外和体内抑制高致瘤性 SCLC 亚群的克隆形成和自我更新。 这些数据表明 KSR2 对于生物体的自我更新和长期传播至关重要。 SCLC 形成所必需的基础神经内分泌群体，将通过 1) 确定进行测试 KSR2 在 PNEC 和 SCLC TPC 自我更新和 SCLC 肿瘤形成中的作用以及 2) 定义 KSR2- 支持 SCLC TPC 自我更新的介导信号通路。