Novel tumorigenic mechanisms of the LKB1 tumor suppressor

 描述(申请人提供)：子宫由体(体)和宫颈组成。尽管宫颈癌和子宫内膜癌发生在同一器官的相邻解剖部位，并且在苗勒氏上皮具有共同的胚胎学起源，但宫颈癌和子宫内膜癌具有非常不同的生物学和临床特征。子宫内膜癌是女性生殖道最常见的癌症，由于肥胖这一重大危险因素的增加，其发病率正在迅速增长。宫颈癌是世界上最常见的癌症之一，是由感染HPV引起的，其次是导致肿瘤进展的致癌基因突变。我们实验室和其他实验室最近的研究表明，通过不同的机制使LKB1肿瘤抑制因子失活是两种类型的子宫癌共同的关键驱动事件。LKB1失活在一定程度上通过AMPK/mTOR信号轴控制代谢促进肿瘤进展，但仅靠这一过程不能完全解释LKB1的所有生物学效应，如LKB1失活与侵袭、转移和不良临床结局之间的强烈关联。我们基于基因工程小鼠模型和人类细胞系研究的广泛的初步数据显示，肿瘤炎症是一种新的但仍然必不可少的由LKB1缺失引发的促肿瘤过程。在这里，我们建议通过一组不同但互补的细胞系模型、基因工程小鼠和使用人类肿瘤标本进行的翻译研究来研究LKB1LKB1的这一未知方面作为肿瘤抑制因子的作用。我们的实验室在我们已经开发的这些小鼠和细胞系模型方面拥有丰富的经验，在生物标记物的开发和人类肿瘤标本的分析方面也有丰富的经验。该项目还将受益于我们的合作者在LKB1、肿瘤-宿主相互作用和细胞迁移方面的集体专业知识。这项工作可能对我们理解LKB1驱动的癌症有深远的影响，并导致对这些高度致命的恶性肿瘤的更好治疗。

 DESCRIPTION (provided by applicant): The uterus consists of the corpus (body) and cervix. Although cervical and endometrial (i.e. corpus) carcinomas arise at adjacent anatomic sites in the same organ and have a common embryologic origin in the Müllerian epithelium, cervical and endometrial carcinomas have very different biological and clinical features. Endometrial cancer is the most common cancer of the female reproductive tract, and its incidence is rapidly growing due to the increase in obesity, a significant risk factor. Cervical cancer, among the most common cancers worldwide, is caused by infection with HPV, followed by the acquisition of oncogenic mutations that drive tumor progression. Studies from our laboratory and others have recently shown that inactivation of the LKB1 tumor suppressor by diverse mechanisms is a common and key driving event shared by both types of uterine cancer. LKB1 inactivation promotes tumor progression in part through its control of metabolism via the AMPK/mTOR signaling axis, but this process alone cannot fully account for all of the biological effects of LKB1, such as the strong association between LKB1 inactivation and invasion, metastasis, and a poor clinical outcome. Our extensive preliminary data-based on genetically-engineered mouse models and human cell line studies-has revealed that tumor inflammation is a novel but nonetheless essential pro-tumorigenic process triggered by LKB1 loss. Here, we propose to study this heretofore unexplored aspect of LKB1's actions as a tumor suppressor through a diverse but complementary set of cell line models, genetically-engineered mice, and translational studies employing human tumor specimens. Our laboratory has extensive experience in these mouse and cell line models, which we have already developed, and also in biomarker development and the analysis of human tumor specimens. This project will also benefit from our collaborators' collective expertise in LKB1, tumor-host interactions, and cell migration. This work could have far-reaching implications for our understanding of LKB1-driven cancers and lead to better treatments against these highly-lethal malignancies.