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Novel tumorigenic mechanisms of the LKB1 tumor suppressor

LKB1抑癌基因的新致瘤机制

基本信息

批准号：
9101758
负责人：
DIEGO H CASTRILLON
金额：
$ 37.02万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9101758
关键词：
Accounting Anatomy Animals Antibodies Apoptosis Automobile Driving Behavior Biological Biological Assay Biology CCL2 gene CSF1 gene CSF1R gene Carcinoma Cell Line Cell Polarity Cell Proliferation Cells Cellular Metabolic Process Cervical Cervix Neoplasms Cervix Uteri Cervix carcinoma Chemotaxis Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytotoxic Chemotherapy Databases Development Endometrial Endometrial Carcinoma Epithelium Event FRAP1 gene Family Feedback Female Freezing Genetic Genetically Engineered Mouse Goals Growth Human Human Cell Line Human Papillomavirus Incidence Infection Inflammation Knock-out Laboratories Lead Lesion Longitudinal Studies Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Metabolism Modeling Molecular Profiling Mouse Cell Line Mus Mutation Neoplasm Metastasis Neoplasms Obesity Oncogenic Organ Outcome Pancreas Phosphotransferases Play Primary Neoplasm Process Production Radiation therapy Recruitment Activity Risk Factors Role STK11 gene Sampling Signal Transduction Skin Cancer Specimen Staging TNF gene Testing Therapeutic Tumor Cell Migration Tumor Suppressor Proteins Uterine Cancer Uterus Wild Type Mouse Work autocrine base biomarker development cancer type cell motility chemokine cohort cytokine density experience host neoplasm interaction in vitro Model interest macrophage malignant phenotype member migration mouse model neglect neoplastic cell novel paracrine programs public health relevance reproductive tract small molecule inhibitor targeted cancer therapy targeted treatment theranostics transcriptome sequencing translational study tumor tumor growth tumor initiation tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

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.