Functions of the LKB1 tumor suppressor in control in metabolism and epigentics

摘要 在多发性上皮性肿瘤中发现LKB 1/STK 11肿瘤抑制基因的失活突变 类型包括~20%的非小细胞肺癌（NSCLC）和~5%的胰腺导管癌 腺癌（PDA）。在NSCLC中，这些突变与对常规化疗的不良反应相关， 靶向和免疫调节治疗。在胰腺肿瘤发生中，LKB 1突变见于 在癌前病变导管内乳头状粘液性肿瘤（IPMN）和PDA中， 预后（Furukawa等人，2007; Yang等人，2015）。我们小组和其他人的工作表明， LKB 1是细胞代谢的中心调节剂（Gurumurthy等人，2009，Kottakis等人，2016）。LKB 1损失 结果增强生物合成过程，同时减少线粒体氧化磷酸化。的 LKB 1突变细胞中代谢重编程的基础尚未完全理解。该提案寻求 探讨LKB 1在线粒体调控中的新作用。我们的初步数据显示， 线粒体功能障碍是LKB 1突变型肿瘤发病机制的核心， 新的治疗弱点在初步研究中，我们发现LKB 1突变体（LKB 1 m）癌细胞 在线粒体结构上表现出惊人的变化，LKB 1直接控制着两个基本的 线粒体稳态的过程-维持线粒体融合和 分裂和激活修复或清除受损线粒体的主要机制。这些 研究结果具有重要的功能意义。我们的初步研究表明， 线粒体融合在LKB 1 m癌细胞中是致命的;这些细胞对线粒体融合高度敏感。 损伤;并且可以进一步利用缺陷线粒体质量控制来恢复抗肿瘤 免疫力从这些研究中出现的总体概念是这些特定的线粒体改变 是LKB 1突变型NSCLC和PDA的标志， 监管将开辟新的治疗方向。 目前的建议集中在这些线粒体表型的一个方面，即线粒体的增加。 LKB 1缺失导致的裂变。线粒体动力学，融合和分裂之间的转换， 在管状和碎片状态之间配置线粒体，其具有不同的代谢输出。 融合导致紧密堆积的嵴，有效的OXPHOS和脂肪酸氧化，而裂变则扩展 嵴，降低OXPHOS效率，促进有氧糖酵解。我们提出的研究将测试 LKB 1缺失导致的线粒体过度碎片化驱动代谢的假设 重编程对于肿瘤发生至关重要。为此，我们将使用 在新的体外和体内模型系统的遗传和药理学方法，我们将测试 从而影响代谢稳态和肿瘤细胞生长和存活。这些研究的结果 将为LKB 1突变型癌症的生物学提供新的见解，并证明潜在的新治疗方法 针对这些肿瘤的策略。

ABSTRACT Inactivating mutations in the LKB1/STK11 tumor suppressor are found across multiple epithelial tumor types including ~20% of non-small cell lung cancers (NSCLC) and ~5% of pancreatic ductal adenocarcinomas (PDA). In NSCLC, these mutations correlate with poor response to conventional, targeted, and immune-modulating treatment. In pancreatic tumorigenesis, LKB1 mutations are found in both in premalignant intraductal papillary mucinous neoplasms (IPMN) and in PDA and also portend a poor prognosis (Furukawa et al., 2007; Yang et al., 2015). Work from our group and others has shown that LKB1 is a central regulator of cell metabolism (Gurumurthy et al., 2009, Kottakis, et al., 2016). LKB1 loss results potentiates biosynthetic processes while reducing mitochondrial oxidative phosphorylation. The basis for metabolic reprogramming in LKB1 mutant cells is incompletely understood. This proposal seeks to explore the novel roles of LKB1 in the regulation of the mitochondria. Our preliminary data indicate that mitochondrial dysfunction is central to the pathogenesis of LKB1 mutant tumors and presents significant new therapeutic vulnerabilities. In preliminary studies, we find that LKB1 mutant (LKB1m) cancer cells exhibit a striking change in mitochondrial architecture and that LKB1 directly controls two fundamental processes of mitochondrial homeostasis—maintaining the balance between mitochondrial fusion and fission and activating the primary mechanism for repair or clearance of damaged mitochondria. These findings have important functional implications. Our preliminary studies indicate that restoration of mitochondrial fusion is lethal in LKB1m cancer cells; that these cells are hypersensitive to mitochondrial insults; and that defective mitochondrial quality control can be further exploited to restore anti-tumor immunity. The overarching concept emerging from these studies is these specific mitochondrial alterations are a hallmark of LKB1 mutant NSCLC and PDA, and that deciphering the mechanisms of mitochondrial regulation will open new therapeutic directions. The present proposal focuses one aspect of these mitochondrial phenotypes, the increase in mitochondrial fission resulting from LKB1 loss. Mitochondrial dynamics, the conversion between fusion and fission, configure mitochondria between tubular and fragmentated states, which have distinct metabolic outputs. Fusion leads to tightly packed cristae, efficient OXPHOS and fatty acid oxidation, whereas fission expands the cristae, reduces OXPHOS efficiency and promotes aerobic glycolysis. Our proposed studies will test the hypothesis that mitochondrial hyper-fragmentation resulting from LKB1 loss drives metabolic reprogramming essential for tumorigenesis. To this end, we will modulate mitochondrial dynamics using genetic and pharmacological approaches in novel in vitro and in vivo model systems, and we will test the resulting impact on metabolic homeostasis and tumor cell growth and survival. Results from these studies will provide new insights into the biology of LKB1 mutant cancers and credential potential new therapeutic strategies against these tumors.