Molecular mechanisms of SCLC initiation and detection in mice and humans

小鼠和人类 SCLC 启动和检测的分子机制

基本信息

批准号：
10469595
负责人：
MARK A KRASNOW
金额：
$ 53.31万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469595
关键词：
Cell Culture Techniques Cells Data Detection Diagnosis Disease Early Diagnosis Early treatment Environment Epithelial Epithelial Cells Event Gene Expression Profile Genetic Genetic Engineering Genetically Engineered Mouse Genomic approach Genomics Goals Human Human Genetics Immune mediated destruction Individual Injury Life Expectancy Limited Stage Lung Malignant Neoplasms Methods Minor Molecular Mus Mutate Mutation Neoplasm Metastasis Neuroendocrine Cell Neuroendocrine Tumors Neuropeptides Neurosecretory Systems Non-Invasive Cancer Detection Oncogenic Paraneoplastic Syndromes Patients Peptides Phase Process Proliferating Resected Resolution Signal Transduction Specimen Survival Rate TP53 gene Time Tumor Suppressor Proteins Widespread Disease base bronchial epithelium cancer stem cell early detection biomarkers effective therapy injured injured airway injury and repair insight lung small cell carcinoma mouse genetics mouse model neoplastic cell neuroendocrine cancer neurosensory new therapeutic target novel novel strategies premalignant programs screening single-cell RNA sequencing stem cell population stem cell proliferation stem cells tumor tumor behavior tumor diagnosis tumor initiation

项目摘要

Small cell lung carcinoma (SCLC) is one of the deadliest cancers, a “recalcitrant” cancer for which there is no effective treatment except when the disease is diagnosed early. However, only a small fraction of patients are diagnosed early in disease. The greatest challenge to early diagnosis is that SCLC tumor cells typically acquire an exceptional mutation burden and metastasize early, so for most patients disease has spread beyond the lung at the time of diagnosis. The key to developing effective early diagnosis and treatment methods is to elucidate the earliest molecular and cellular events of tumor initiation to uncover ones that can be detected by screening during the premalignant phase of the disease. The goal of this proposal is to define the early, premalignant molecular and cellular events of SCLC, so that they can be detected early and destroyed before they become a deadly, untreatable disease. SCLC is a neuroendocrine cancer. The prominent cell of origin is pulmonary neuroendocrine (NE) cells, neurosensory and neurosecretory epithelial cells that sense and respond to the environment in the lung. Recently, a minor subpopulation of NE cells was found to have stem cell activity, proliferating, dispersing, and replenishing the surrounding bronchial epithelium following severe airway injury. Loss of tumor suppressors Rb and p53 constitutively activates the stem cell program within days of loss of the tumor suppressors, even in the absence of injury. In this proposal, a combination of genetics, cell culture, and single-cell genomics is used to systematically interrogate these stem cells at cellular resolution, both in healthy lungs and in the early, premalignant stage of SCLC. The goal is to define the molecular events immediately following loss of Rb and p53 that constitutively activate the stem cell program and initiate their transformation into cancer stem cells that spread, mutate, and escape immune destruction, and to identify the signals they secrete that might allow the tumors to be detected before they become deadly.

小细胞肺癌（SCLC）是最致命的癌症之一，是一种“顽固性”癌症除了早期诊断出疾病外，没有有效的治疗方法。但是，只有一小部分患者在疾病早期被诊断出。早期诊断的最大挑战是SCLC肿瘤细胞通常获得特殊的突变烧伤和早期转移，因此对于大多数患者而言，疾病已经扩散诊断时肺部超出肺部。发展有效的早期诊断和治疗的关键方法是阐明肿瘤倡议的最早分子和细胞事件，以发现可以可以通过在疾病的临时阶段进行筛查来检测。该提议的目的是定义 SCLC的早期，预典型的分子和细胞事件，因此可以早期检测到它们在它们成为一种致命，不可治疗的疾病之前被摧毁。 SCLC是一种神经内分泌癌。原始细胞是肺神经内分泌（NE）细胞，对肺部环境感知并反应的神经感觉和神经分泌上皮细胞。最近，发现NE细胞的小亚群具有干细胞活性，增殖，分散和严重气道受伤后，补充周围的支气管上皮。肿瘤补充RB的损失和p53在肿瘤补充剂丧失后的几天内，组成型激活干细胞程序，即使在没有伤害。在此提案中，遗传学，细胞培养和单细胞基因组学的结合用于在健康的肺和早期，系统地在细胞分辨率下系统地询问这些干细胞 SCLC前阶段。目的是在损失RB和RB后立即定义分子事件组成性激活干细胞程序并将其转化为癌症干细胞的p53 传播，突变和逃避免疫破坏，并确定它们秘密的信号，以便允许肿瘤在致命之前要检测到。