Novel tumorigenic mechanisms of the LKB1 tumor suppressor

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 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.