Novel tumorigenic mechanisms of the LKB1 tumor suppressor

 描述（由申请人提供）：子宫由子宫体和子宫颈组成。虽然子宫颈癌和子宫内膜癌（即子宫体癌）发生在同一器官的相邻解剖部位，并且在苗勒管上皮中具有共同的胚胎起源，但子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，其发病率由于肥胖的增加而迅速增长，肥胖是一个重要的危险因素。宫颈癌是世界上最常见的癌症之一，由HPV感染引起，其次是获得致癌突变，从而推动肿瘤进展。我们实验室和其他人的研究最近表明，LKB 1肿瘤抑制因子通过不同机制失活是两种类型子宫癌共有的常见和关键驱动事件。 LKB 1失活部分地通过其经由AMPK/mTOR信号传导轴的代谢控制来促进肿瘤进展，但仅此过程不能完全解释LKB 1的所有生物学效应，例如LKB 1失活与侵袭、转移和不良临床结果之间的强关联。我们基于基因工程小鼠模型和人类细胞系研究的大量初步数据表明，肿瘤炎症是一种新的但仍然是由LKB 1丢失引发的重要促肿瘤发生过程。在这里，我们建议通过一组不同但互补的细胞系模型、基因工程小鼠和采用人类肿瘤标本的翻译研究来研究LKB 1作为肿瘤抑制因子的作用这一迄今尚未探索的方面。 我们的实验室在我们已经开发的这些小鼠和细胞系模型以及生物标志物开发和人类肿瘤标本分析方面拥有丰富的经验。该项目还将受益于我们合作者在LKB 1，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LKB 1驱动的癌症产生深远的影响，并导致更好地治疗这些高致命性恶性肿瘤。

 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.