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.

描述（由适用提供）：子宫由语料库（身体）和子宫颈组成。尽管宫颈和子宫内膜（即语料库）癌在同一器官的相邻解剖部位出现，并且在Müllerian上皮中具有共同的胚胎学起源，但宫颈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的最常见癌症，由于肥胖症的增加，其发病率正在迅速增长，这是一个重要的危险因素。宫颈癌是全球最常见的癌症之一，是由HPV感染引起的，随后是促进肿瘤进展的致癌突变。我们实验室和其他人的研究最近表明，通过潜水机制对LKB1肿瘤抑制剂的失活是两种类型的子宫癌共有的常见且关键的驾驶事件。 LKB1失活通过AMPK/MTOR信号轴来促进肿瘤的进展，部分促进了其代谢，但是仅此过程无法完全考虑LKB1的所有生物学作用，例如LKB1失活和入侵和入侵，转移，转移和临床不良结果之间的牢固关联。我们广泛的基于基于遗传学的小鼠模型和人类细胞系研究的初步数据表明，肿瘤注射是一种新颖但仍是由LKB1损失触发的必不可少的促肿瘤过程。在这里，我们建议通过多样性，但完整的细胞系模型，遗传学工程的小鼠以及使用人类肿瘤标本的翻译研究来研究LKB1作为肿瘤抑制器的这一意想不到的方面。我们的实验室在我们已经开发的这些小鼠和细胞系模型中以及生物标志物发育和人类肿瘤标本的分析方面具有丰富的经验。该项目还将受益于我们合作者在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对LKB1驱动的癌症的理解具有深远的影响，并为这些高度致命的恶性肿瘤提供更好的治疗方法。