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Molecular dissection of Lkb1-mediated tumor suppression

Lkb1介导的肿瘤抑制的分子解剖

基本信息

批准号：
10405647
负责人：
Monte Meier Winslow
金额：
$ 40.98万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405647
关键词：
Address Alleles Biological Models CRISPR/Cas technology Cancer Etiology Cancer Model Cell Culture Techniques Cell physiology Cessation of life Chromatin Country Data Development Dissection Environment Enzymes Epigenetic Process Family Gene Expression Genes Genetic Genetic Epistasis Genetically Engineered Mouse Genomics Genotype Goals Growth Health Histology Human Immunohistochemistry KRAS oncogenesis Link Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Methods Molecular Molecular Analysis Molecular Conformation Mus Mutate Mutation Output Pathway interactions Patients Phosphotransferases Positioning Attribute Protein-Serine-Threonine Kinases Regulation Research STK11 gene System Tumor Biology Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins United States Woman base cancer cell cancer genome cancer type experimental study gene function genome editing genome sequencing genome-wide histone modification in vivo in vivo imaging individualized medicine innovation insight interest loss of function lung cancer cell men new therapeutic target novel personalized cancer therapy precision oncology response restoration somatic cell gene editing therapeutic target tool tumor tumor growth tumor initiation tumor progression tumorigenic

项目摘要

! PROJECT SUMMARY Lung cancer is the leading cause of cancer deaths in both men and women in the United States, with over 155,000 patients dying each year in this country alone. Cancer genome sequencing has begun to uncover the compendium of mutations within human lung adenocarcinoma, but despite these advances we still have a very limited understanding of the molecular and cellular mechanisms by which even the most frequently mutated genes drive cancer growth. In particular, the molecular and cellular consequences of tumor suppressor gene function have been difficult to understand, slowing our understanding of these pathways and stalling personalized oncology approaches aimed at tailoring therapies based on tumor suppressor genotypes. In this proposal, we will employ several innovative methods to uncover the mechanisms by which the Lkb1 tumor suppression constrains lung cancer growth. This will enable a detailed understanding of the tumor suppressive function of Lkb1. While current tools have led to important insights into tumor biology, the inability to restore tumor-suppressor genes of interest at will in established tumors in vivo, has hampered our understanding of their molecular and cellular functions. We have generated mice with a conditionally-inactivable and conditionally-restorable genetic system which allows Lkb1 inactivation and subsequent restoration in autochthonous tumors. To characterize Lkb1-mediated tumor suppression, we will use this allele system to restore Lkb1 expression in lung tumors in vivo. Cellular and molecular analysis both in cell culture and in vivo will extend preliminary findings which linkLkb1 to changes in chromatin accessibility. To further understand the impact of the chromatin landscape on Lkb1-mediated tumor suppression, we will perform cell culture and in vivo experiments focused on the epistatic relationship between Lkb1 and epigenetic modifying enzymes identified in a genome-scale screen for suppressors of Lkb1-mediated growth suppression. Finally, we will investigate the relative importance of the Sik family of kinases which we have found to be tumor suppressive Lkb1-substrates. Our overall goals are to understand the molecular and cellular responses of lung tumors to Lkb1/Sik-mediated tumor suppression as well as to uncover how this response is related to changes in chromatin state. Our preliminary data, novel genetic systems, and strong collaborative team make us uniquely positioned to conduct these studies. Our proposed research is significant because it will increase our fundamental understanding of how Lkb1 limits lung tumor growth, illuminate the connection between Lkb1 and chromatin state dynamics, and potentially uncover novel and therapeutically targetable pro-tumorigenic pathways. !

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项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma.

癌基因阴性肺腺癌的完全可访问的健身景观。

DOI：
10.1073/pnas.2303224120
发表时间：
2023
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Yousefi,Maryam;Andrejka,Laura;Szamecz,Márton;Winslow,MonteM;Petrov,DmitriA;Boross,Gábor
通讯作者：
Boross,Gábor