INDUCIBLE MOUSE MODELS FOR SKIN AND HEAD AND NECK CANCER

描述(由申请人提供)： 该项目的总体目标是产生可诱导的小鼠模型，接近模拟人类皮肤癌和头颈癌的发展。我和我的同事最近开发了可诱导的小鼠模型，允许在皮肤、口腔或食道的有限区域激活癌基因或灭活干细胞中的肿瘤抑制基因，以更新这些复层上皮。因此，我们可以创造出体细胞发生离散基因变化的小鼠，这些变化与人们认为发生在人类肿瘤中的事件相同。 迄今为止发现的基因变化主要与肿瘤发展的早期阶段有关。人们对肿瘤进展为转移性病变时发生的基因变化知之甚少。因此，我们的应用将集中在最近发现的候选基因，这些候选基因通过依赖和独立于基因组不稳定性的机制促进肿瘤进展。 为了在我们的可诱导小鼠模型中识别与肿瘤进展相关的新的基因变化，我们将使用Affymetrix阵列和BAC/CGH阵列来分析肿瘤。在平行研究中，我们还将使用Affymetrix阵列和BAC/CGH阵列分析具有侵袭性和转移倾向的人类皮肤和头颈部肿瘤，并将这些发现与对小鼠肿瘤的分析结果进行比较。 我们的可诱导小鼠模型由于离散的遗传变化而发生肿瘤，因此这些模型非常适合测试旨在干扰特定基因产物或信号通路的新型药物。将进行初步实验，以评估这些模型作为翻译研究工具的实用性。在这些研究中，成像将被用于早期发现转移灶并监测治疗后的消退。

DESCRIPTION (provided by applicant): The overall objective of this project is the generation of inducible mouse models that closely mimic the development of human skin and head and neck cancers. My colleagues and I have recently developed inducible mouse models that allow the activation of oncogenes or inactivation of tumor suppressor genes in a restricted area of the skin, oral cavity or esophagus in stem cells that renew these stratified epithelia. Thus, we can create mice with discrete genetic changes in somatic cells that are identical to events that are thought to occur in human tumors. The genetic changes identified to date are primarily associated with early stages of tumor development. Much less is known about genetic changes that occur as tumors progress to metastatic lesions. Thus, our application will focus on recently discovered candidate genes implicated in promoting tumor progression through mechanisms that are both dependent on and independent of genomic instability. To identify novel genetic changes associated with tumor progression in our inducible mouse models, we will analyze tumors using both Affymetrix arrays and BAC/CGH arrays. In parallel studies, we will also analyze human skin and head and neck tumors which exhibit an aggressive nature and propensity to metastasize by Affymetrix arrays and BAC/CGH arrays and compare these findings with results obtained from analysis of the mouse tumors. Our inducible mouse models develop tumors as the result of discrete genetic changes, therefore these models are ideally suited to test novel drugs designed to interfere with specific gene products or signaling pathways. Pilot experiments will be performed to assess the utility of these models as tools for translational studies. Imaging will be utilized for the early detection of metastatic lesions in these studies and to monitor regression following treatment.