Sox9 signaling in lung adenocarcinoma

描述（由申请人提供）：肿瘤经常利用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，我们正专注于Sox9的潜在作用，这是一种人类发育所需的转录因子。我们发现Sox9在正常肺组织中几乎不表达，但在原发性人和小鼠肺肿瘤以及肺癌细胞系中却过表达。我们发现Sox9不仅是Notch1信号的直接靶基因，也是Notch1诱导的间充质样细胞形态学改变、E- cadherin抑制、细胞运动和肺癌侵袭的关键介质。我们的研究表明，Sox9是其他致癌途径的下游。我们提出Sox9是上游致癌信号汇聚的终端枢纽，并在介导其对肺肿瘤发生和进展的贡献中发挥核心作用。因此，靶向Sox9表达可以减轻靶向治疗过程中冗余致癌途径引起的耐药。本提案的总体目标是验证调节Sox9表达和介导Sox9在诱导细胞运动和侵袭中的作用的途径。我们将测试Sox9在小鼠lun癌变过程中的功能。利用患者来源的肺肿瘤异种移植物和经过验证的平台在体内靶向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肿瘤进展的调控，并制定一种潜在的规避治疗耐药性的策略。

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.