Novel Mechanisms Controlling SCLC Tumor Initiation

控制 SCLC 肿瘤发生的新机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要 /摘要该项目的目的是确定小细胞肺癌（SCLC）的新分子决定因素肿瘤发展。关于启动的分子机制，知之甚少在这种高度侵略性，转移性和致命性肺癌中，肿瘤质量。几乎所有SCLC患者是或烟民。编码肿瘤抑制剂TP53和 RB1发生在几乎所有SCLC肿瘤中。此外，最近已显示TP53和RB1以限制肺神经内分泌细胞（PNEC）的自我更新，它是SCLC的起源细胞。尽管有这些对SCLC分子发病机理必不可少的遗传改变的文献有效治疗靶标的识别受到限制。 SCLC独有的关键漏洞检测将是消除肺癌死亡的重大进步。一个潜在的贡献者导致SCLC发育的肿瘤塑性是RAS 2（KSR2）的分子支架激酶抑制剂。我们的分析表明，在正常肺组织中，分子支架KSR2是无法检测的，但很牢固以PNEC和SCLC细胞系表示，主要是最常见的Achaete-Scute复合物同源1（ASCL1）亚型。这种相关性与发展和发展的相关性先前的观察结果暗示（1）CHIP-SEQ分析表明KSR2是A SCLC中ASCL1的转录靶标，（2）ASCL1对于正常肺的发展至关重要神经内分泌细胞和SCLC内的肿瘤发射能力。同样，KSR2明显敲除在体外和体内抑制高度肿瘤的SCLC亚群中的克隆原性和自我更新。这些数据表明，KSR2对于自我更新和长期传播至关重要 SCLC形成必不可少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肿瘤形成以及2）定义KSR2-的作用支持SCLC TPC自我更新的介导信号通路。