Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis

肺腺癌肿瘤发生中的异常糖原

• 批准号: 10748000
• 负责人: Matthew S. Gentry
• 金额: $ 49.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748000
• 关键词: Aberrant; Glycogen; Lung; Adenocarcinoma; Tumorigenesis

Abstract: Lung adenocarcinoma (LUAD) is the major histological subtype of lung cancer and the leading cause of cancer-related mortalities worldwide. For a substantial number of LUAD patients, the only treatment options available are traditional multi-agent chemotherapy coupled with surgery and/or radiation. For these patients, the 5-year survival remains disappointingly low. Additional molecular mechanisms driving LUAD proliferation and tumorigenesis remain a critical knowledge gap in lung cancer research, and a major barrier for the development of personalized therapies. Recent reports, including our own, reveal critical roles for glycogen in lung tumor progression. Building on these foundational studies, we developed a robust and precision technology to visualize glycogen in situ with 50 µm spatial resolution using mass spectrometry imaging that provides 1,000x increased sensitivity compared to previous methods. Using this technology, we defined glycogen levels in 122 NSCLC patients treated at the University of Kentucky’s NCI Designated Cancer Center. Our preliminary data demonstrate that: 1) significantly elevated glycogen is observed in LUAD and not in normal lung tissue. 2) Elevated glycogen is a LUAD tissue-specific hallmark and is not observed in lung squamous cell carcinoma. 3) LUAD-glycogen is structurally unique with increased phosphorylation and branching. 4) This LUAD phenotype correlated with marked protein decreases in the glycogen phosphatase laforin. Strikingly, laforin knockout in model lung cell lines and the KrasG12D/p53-/- LUAD mouse model drives: 1) glycogen hyper-phosphorylation, 2) increased affinity with the master metabolic regulator AMP-activated protein kinase (AMPK), 3) decreased AMPK activity, and 4) accelerated tumor proliferation and progression. We hypothesize that the structurally unique LUAD-glycogen is a critical component of LUAD metabolism, proliferation, and progression. The overall objective of this study is to define the etiology of LUAD-glycogen on both cancer metabolism and tumor progression. To achieve this, we will: Define the LUAD-glycogen clinical course and its interaction with AMPK (Aim 1). Then, we will define the signaling role of LUAD-glycogen in cellular metabolism through AMPK (Aim 2). Finally, we will establish the role of LUAD-glycogen in tumor progression and early transformation in vivo (Aim3). This proposal builds on exciting and rigorous preliminary data and presents an integrated approach to define this unique LUAD hallmark of excess glycogen utilizing robust, complementary, and state-of-the-art methodologies such as mass spectrometry imaging, protein and glycogen biochemistry, and targeted metabolomics. The salient findings from this proposal will significantly advance the knowledge base regarding the roles of glycogen in LUAD biology and progression and drive the discovery of personalized therapies that can be leveraged for the LUAD population that only qualify for conventional chemotherapy.

抽象的： 肺腺癌（LUAD）是肺癌的主要组织学亚型，也是主要原因 全球与癌症有关的死亡率。对于大量的LUAD患者，唯一的治疗选择 可用的是传统的多药化疗以及手术和/或辐射。对于这些患者， 5年的生存仍然令人失望。驱动luad增殖的其他分子机制 肿瘤发生在肺癌研究中仍然是一个关键的知识差距，这是 开发个性化疗法。最近的报告，包括我们自己的，揭示了糖原在 肺部肿瘤进展。在这些基础研究的基础上，我们开发了强大而精确的 使用质谱成像，以50 µm空间分辨率来可视化糖原原位的技术 与以前的方法相比，具有1,000倍的灵敏度。使用此技术，我们定义了 肯塔基大学NCI指定癌症中心接受治疗的122名NSCLC患者的糖原水平。 我们的初步数据表明：1）在luad中观察到糖原显着升高，而不是在 正常的肺组织。 2）升高的糖原是luad组织特异性标志，在肺中未观察到 鳞状细胞癌。 3）LUAD-糖原在结构上是独特的，随着磷酸化的增加和 分枝。 4）这种LUAD表型与糖原磷酸酶的明显蛋白质下降相关 拉福林。令人惊讶的是，模型肺细胞系中的Laforin淘汰赛和KRASG12D/p53 - / - LUAD小鼠模型驱动器：1） 糖原高磷酸化，2）增加与主代谢调节剂AMP激活的亲和力增加 蛋白激酶（AMPK），3）改善AMPK活性，4）加速肿瘤增殖和进展。 我们假设在结构上独特的luAd-基糖原是LUAD代谢的关键组成部分， 增殖和进展。这项研究的总体目的是定义luAD-糖原的病因 癌症的代谢和肿瘤进展。为了实现这一目标，我们将：定义LUAD-Glycogen临床 课程及其与AMPK的互动（AIM 1）。然后，我们将定义luAD-糖原在 通过AMPK的细胞代谢（AIM 2）。最后，我们将确定luAD-糖原在肿瘤中的作用 体内进展和早期转化（AIM3）。该提案以令人兴奋而严格的初步为基础 数据并提出了一种综合方法来定义使用过多糖原的独特luad标志 健壮，完整和最先进的方法，例如质谱成像，蛋白质和 糖原生物化学和靶向代谢组学。该提议的显着发现将大大显着 促进有关糖原在luad生物学和进展中的作用的知识基础，并推动 发现只有资格的LUAD人群可以利用的个性化疗法 常规化学疗法。