Molecular dissection of Lkb1-mediated tumor suppression

好了！ 项目总结 肺癌是美国男性和女性癌症死亡的主要原因，超过 仅在这个国家，每年就有155,000名患者死亡。癌症基因组测序已经开始揭示 人类肺腺癌内突变的概要，但尽管有这些进展，我们仍然有一个非常 对分子和细胞机制的了解有限，即使是最频繁的突变 基因驱动着癌症的生长。特别是，肿瘤抑制基因的分子和细胞后果 功能一直很难理解，减慢了我们对这些路径的理解并停滞不前 个人化肿瘤学方法旨在根据肿瘤抑制基因类型定制治疗方法。在这 我们将使用几种创新的方法来揭示Lkb1肿瘤的机制 抑制会抑制肺癌的生长。这将使对肿瘤抑制的详细了解成为可能 Lkb1的功能。虽然目前的工具已经导致了对肿瘤生物学的重要洞察，但无法恢复 在体内已建立的肿瘤中随意发现感兴趣的肿瘤抑制基因，阻碍了我们对 它们的分子和细胞功能。我们已经产生了一种有条件失活和 有条件恢复的遗传系统，允许Lkb1失活和随后在 原发肿瘤。为了表征Lkb1介导的肿瘤抑制，我们将使用这个等位基因系统来 体内恢复肺癌组织中Lkb1的表达。细胞培养和体内的细胞和分子分析 将扩大将Lkb1与染色质可及性变化联系起来的初步发现。为了进一步了解 染色质景观对Lkb1介导的肿瘤抑制的影响，我们将进行细胞培养和 体内实验侧重于Lkb1和表观遗传修饰酶的上位关系 在基因组规模的筛选中发现了Lkb1介导的生长抑制因子。最后，我们会 研究我们已发现的抑制肿瘤的SIK蛋白家族的相对重要性 LKB1-底物。我们的总体目标是了解肺癌的分子和细胞反应 LKB1/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、新颖的基因系统和强大的协作团队使我们独一无二 有能力进行这些研究。我们提出的研究具有重要意义，因为它将增加我们的 对Lkb1如何限制肺癌生长的基本了解，阐明了Lkb1和Lkb1之间的联系 染色质状态动态，并可能发现新的和具有治疗靶向性的促肿瘤作用 小路。 好了！

! 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. !