CELLS OF ORIGIN OF LUNG CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目标1：检验假设，不同位置的Clara细胞亚群会导致不同表型的腺癌 人类呼吸道中的Clara细胞代表了腺癌的潜在干细胞来源。我们已经建立了一个在不同位置表达Scgb1a1(CC10)的分泌细胞(Clara)中K-RasG12D激活的小鼠模型：远端肺和BADJ，较大的呼吸道和气管。我们发现，这些小鼠在支气管肺泡管交界处周围出现表面活性蛋白C(SPC)阳性肿瘤，但在近端呼吸道也有大部分SPC阴性肿瘤。我们将分离每种类型的肿瘤，并将它们的转录组图谱相互比较，并与分离的野生型Clara细胞进行比较。这将提供对与起源细胞相关的肿瘤生物学的潜在差异的洞察。 目标2：验证潜在致癌转录因子Sox2和Nkx2.1与Kras突变体在Clara细胞和其他支气管上皮细胞中共表达导致不同组织学和行为的肿瘤的假设。 最近来自人类肿瘤的数据表明，Nkx2.1(TTF1)和SOX2分别是腺癌和鳞癌的潜在癌基因。我们已经建立了携带可诱导的Nkx2.1或Sox2等位基因的小鼠系，并开始将它们与CC10Creer-Kras突变小鼠杂交。此外，与K5Creer、SPCCreer和FoxJ1Creer的杂交正在进行中。由此产生的肿瘤，如果有的话，将被调查的位置，组织学，生长速度，和转录组图谱。 目的3：验证RAS基因驱动的转基因小鼠肺腺癌对某些化疗药物的敏感性以及治疗后敏感性会发生改变的假设。RAS突变诱导的肿瘤的转录组图谱将与杜克大学使用肿瘤细胞系产生的几个已知的化疗敏感性图谱进行比较。这些小鼠将被注射预计对它们敏感或耐药的药物。将调查小鼠的存活情况以及残留肿瘤的基因组图谱。

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.