Sox9 signaling in lung adenocarcinoma

描述(申请人提供)：肿瘤经常征集发育基因，将致癌信号转化为肿瘤进展的驱动因素。为了更好地了解肺癌发生和发展背后的分子机制，我们将重点放在Sox9的潜在作用上，Sox9是人类发育所需的一种转录因子。我们发现，Sox9在正常肺组织中几乎不表达，但在原发的人和小鼠肺肿瘤以及肺癌细胞系中过表达。我们确定Sox9不仅是Notch1信号转导的直接靶基因，而且也是Notch1诱导的间充质样细胞形态改变、E-钙粘附素抑制、细胞运动和肺癌侵袭的关键介质。我们的研究表明，Sox9位于其他致癌途径的下游。我们认为Sox9是上游致癌信号汇聚的末端枢纽，并在介导它们在肺部肿瘤发生和发展中的作用发挥核心作用。因此，靶向Sox9表达可以减轻靶向治疗期间多余的致癌途径经常引发的耐药性。该方案的总体目标是验证调控Sox9表达的途径以及介导Sox9的S在诱导细胞运动和侵袭中的作用。我们将检测Sox9在小鼠肺癌发生过程中的作用。使用患者来源的肺肿瘤异种移植和一个有效的平台在体内靶向Sox9，我们将测试Sox9抑制是否具有抗肿瘤活性。这项研究将有助于理解一种新的胚胎发育基因对肺癌进展的调控，并开发一种潜在的规避治疗耐药的策略。

DESCRIPTION (provided by applicant): Tumors frequently enlist developmental genes to translate oncogenic signals into drivers of tumor progression. To gain a better understanding of the molecular mechanisms behind lung carcinogenesis and progression, we are focusing on the potential role of Sox9, a transcription factor required for human development. We found that Sox9 is barely expressed in normal lung tissue, but is overexpressed in primary human and murine lung tumors as well as lung cancer cell lines. We determined that Sox9 is not only a direct target gene of Notch1 signaling, but it is also a key mediator of Notch1-induced mesenchymal-like cellular morphological changes, E- cadherin repression, cell motility, and invasion in lung cancer. Our studies suggest that Sox9 is downstream of other oncogenic pathways. We propose that Sox9 is a terminal hub for convergence of upstream oncogenic signals, and plays a central role in mediating their contribution to lung tumorigenesis and progression. Therefore, targeting Sox9 expression could alleviate the resistance often invoked by redundant oncogenic pathways during treatment with targeted therapies. The overall goals of this proposal are to validate the pathways regulating Sox9 expression and mediating Sox9's role in the induction of cell motility and invasion. We will test the function of Sox9 during murine lun carcinogenesis. Using patient-derived lung tumor xenografts and a validated platform to target Sox9 in vivo, we will test if Sox9 repression has anti-tumor activity. This study will help in understanding the regulation of lung tumor progression by a novel embryonic developmental gene and develop a strategy for potentially circumventing therapeutic resistance.