CELLS OF ORIGIN OF LUNG CANCER

肺癌起源细胞

• 批准号: 7956942
• 负责人: Mark Onaitis
• 金额: $ 0.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956942
• 关键词: Adenocarcinoma; Aftercare; Alleles; Behavior; Cells; Clara cell; Computer Retrieval of Information on Scientific Projects Database; Distal; Duct (organ) structure; Epithelial Cells; Funding; Gene Expression Profile; Genomics; Goals; Grant; Growth; Histology; Human; Institution; Location; Lung; Lung Adenocarcinoma; Malignant neoplasm of lung; Microscopy; Mus; Mutant Strains Mice; Oncogenes; Oncogenic; Phenotype; Predisposition; Pulmonary Surfactant-Associated Protein C; Research; Research Personnel; Residual Tumors; Resistance; Resources; Source; Squamous cell carcinoma; Stem cells; Testing; Trachea; Transgenic Mice; Tumor Biology; Tumor Cell Line; United States National Institutes of Health; chemotherapeutic agent; human data; insight; mouse model; mutant; transcription factor; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Goal 1: To test the hypothesis that subsets of Clara cells in different locations give rise to adenocarcinomas of different phenotypes Clara cells in human airways represent a potential stem cell-of-origin for adenocarcinoma. We have generated a mouse model for activation of K-RasG12D in secretory (Clara) cells expressing Scgb1a1(CC10) in different locations: the distal lung and BADJ, the larger airway, and the trachea. We found that these mice develop surfactant protein C (SPC)-positive tumors around the bronchoalveolar duct junction but also largely SPC-negative tumors in the proximal airways. We will isolate tumors of each type and compare their transcriptome profiles to each other and to isolated wild-type Clara cells. This will provide insight into potential differences in tumor biology related to cell of origin. Goal 2: To test the hypothesis that coexpression of potentially oncogenic transcription factors Sox2 and Nkx2.1 with the Kras mutant in Clara cells and other bronchial epithelial cells leads to tumors of different histologies and behaviors. Recent data from human tumors has implicated NKX2.1 (TTF1) and SOX2 as potential oncogenes in adenocarcinoma and squamous cell carcinoma respectively. We have generated mouse lines carrying inducible Nkx2.1 or Sox2 alleles and have begun crossing them to the CC10CreER-Kras mutant mice. In addition, crosses to K5CreER, SPCCreER, and FoxJ1CreER are underway. The resulting tumors, if any, will be investigated for location, histology, growth rate, and transcriptome profile. Goal 3: To test the hypothesis that Ras-driven transgenic mouse lung adenocarcinoma will be susceptible to certain chemotherapeutic agents and that susceptibility will change after treatment. The transcriptome profile of the Ras mutant-induced tumors will be compared to several known chemotherapeutic sensitivity profiles generated using tumor cell lines at Duke. The mice will be administered agents to which they are predicted sensitive or resistant. The survival of the mice as well as the genomic profiles of residual tumors will be investigated.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目标1：检验不同位置的Clara细胞亚群引起不同表型的腺癌的假设 人气道中的Clara细胞代表腺癌的潜在干细胞来源。我们已经生成了一个小鼠模型，用于激活不同位置表达Scgb 1a 1（CC 10）的分泌（Clara）细胞中的K-RasG 12 D：远端肺和BADJ，较大的气道和气管。我们发现这些小鼠在支气管肺泡管连接处周围发生表面活性蛋白C（SPC）阳性肿瘤，但在近端气道中也主要发生SPC阴性肿瘤。 我们将分离每种类型的肿瘤，并将它们的转录组谱相互比较，并与分离的野生型Clara细胞进行比较。这将深入了解与起源细胞相关的肿瘤生物学的潜在差异。 目标2：为了检验潜在致癌转录因子Sox 2和Nkx 2.1与克拉拉细胞和其他支气管上皮细胞中的Kras突变体的共表达导致不同组织学和行为的肿瘤的假设。 最近的人类肿瘤数据表明，NKX2.1（TTF 1）和SOX 2分别是腺癌和鳞状细胞癌的潜在癌基因。 我们已经产生了携带诱导型Nkx2.1或Sox 2等位基因的小鼠品系，并开始将它们与CC 10 CreER-Kras突变小鼠杂交。 此外，与K5 CreER、SPCCreER和FoxJ 1CreER的杂交正在进行中。 将研究所得肿瘤（如有）的位置、组织学、生长速率和转录组特征。 目标3：检验Ras驱动的转基因小鼠肺腺癌对某些化疗药物敏感以及治疗后敏感性改变的假设。Ras突变体诱导的肿瘤的转录组谱将与在杜克使用肿瘤细胞系产生的几种已知的化疗敏感性谱进行比较。 将向小鼠施用预测它们对其敏感或耐药的药剂。将研究小鼠的存活率以及残留肿瘤的基因组谱。