Molecular dissection of Lkb1-mediated tumor suppression

Lkb1介导的肿瘤抑制的分子解剖

• 批准号: 10158018
• 负责人: Monte Meier Winslow
• 金额: $ 41.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158018
• 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

! 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. !

! 项目摘要 肺癌是美国男性和女性癌症死亡的主要原因， 光是这个国家每年就有15.5万病人死亡。癌症基因组测序已经开始揭示 人类肺腺癌中突变的概要，但尽管有这些进展，我们仍然有一个非常 对即使是最频繁突变的细胞的分子和细胞机制的理解有限， 基因驱动癌症生长。特别是，肿瘤抑制基因的分子和细胞后果 功能一直难以理解，减缓了我们对这些途径的理解， 个性化肿瘤学方法，旨在根据肿瘤抑制基因型定制治疗。在这 我们将采用几种创新的方法来揭示Lkb 1肿瘤的机制， 抑制抑制肺癌生长。这将使我们能够详细了解肿瘤的抑制作用。 LKB 1的功能。虽然目前的工具已经导致了对肿瘤生物学的重要见解，但无法恢复 肿瘤抑制基因的兴趣在体内建立肿瘤，阻碍了我们的理解， 它们的分子和细胞功能。我们已经产生了一种条件性失活的小鼠， 有条件的遗传系统，允许Lkb 1失活和随后的恢复， 自体肿瘤。为了表征Lkb 1介导的肿瘤抑制，我们将使用该等位基因系统来 恢复体内肺肿瘤中Lkb 1的表达。细胞培养和体内的细胞和分子分析 将扩大初步的调查结果，链接Lkb 1染色质可及性的变化。进一步了解 为了研究染色质景观对Lkb 1介导的肿瘤抑制的影响，我们将进行细胞培养， 体内实验集中在Lkb 1和表观遗传修饰酶之间的上位关系 在Lkb 1介导的生长抑制的抑制基因组规模的屏幕上确定。最后我们将 研究我们发现具有肿瘤抑制作用的Sik激酶家族的相对重要性 Lkb 1-底物。我们的总体目标是了解肺肿瘤的分子和细胞反应， Lkb 1/Sik介导的肿瘤抑制，以及揭示这种反应如何与 染色质状态我们的初步数据，新颖的遗传系统和强大的合作团队使我们独一无二 来进行这些研究。我们提出的研究是重要的，因为它将增加我们的 基本了解Lkb 1如何限制肺肿瘤生长，阐明Lkb 1与 染色质状态动力学，并可能揭示新的和治疗靶向的促肿瘤 途径。 !