Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis

摘要： 肺腺癌（LUAD）是肺癌的主要组织学亚型，也是肺癌的主要原因。 全球癌症相关死亡率。对于大量 LUAD 患者来说，唯一的治疗选择 可用的是传统的多药化疗结合手术和/或放疗。对于这些患者来说， 5年生存率仍然低得令人失望。驱动 LUAD 增殖的其他分子机制 和肿瘤发生仍然是肺癌研究中的一个关键知识空白，也是肺癌研究的一个主要障碍 个性化疗法的发展。最近的报告，包括我们自己的报告，揭示了糖原在以下方面的关键作用： 肺部肿瘤进展。在这些基础研究的基础上，我们开发了强大且精确的 使用质谱成像以 50 µm 空间分辨率原位可视化糖原的技术 与以前的方法相比，灵敏度提高了 1,000 倍。使用这项技术，我们定义了 肯塔基大学 NCI 指定癌症中心治疗的 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，而在 正常肺组织。 2) 糖原升高是 LUAD 组织特异性标志，在肺中未观察到 鳞状细胞癌。 3) LUAD-糖原结构独特，磷酸化程度增加， 分支。 4) 这种 LUAD 表型与糖原磷酸酶中蛋白质的显着降低相关 拉福林。引人注目的是，模型肺细胞系和 KrasG12D/p53-/- LUAD 小鼠模型中的 laforin 敲除驱动：1) 糖原过度磷酸化，2) 与主代谢调节剂 AMP 激活的亲和力增加 蛋白激酶 (AMPK)，3) 降低 AMPK 活性，4) 加速肿瘤增殖和进展。 我们假设结构独特的 LUAD 糖原是 LUAD 代谢的关键组成部分， 增殖和进展。本研究的总体目标是确定 LUAD-糖原的病因学 癌症代谢和肿瘤进展。为了实现这一目标，我们将： 定义 LUAD-糖原临床 课程及其与 AMPK 的相互作用（目标 1）。然后，我们将定义 LUAD-糖原在 通过 AMPK 进行细胞代谢（目标 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）。该提案建立在令人兴奋且严格的初步基础上 数据并提出了一种综合方法来定义过量糖原利用的独特 LUAD 标志 稳健、互补且最先进的方法，例如质谱成像、蛋白质和 糖原生物化学和靶向代谢组学。该提案的显着发现将显着 推进有关糖原在 LUAD 生物学和进展中的作用的知识库，并推动 发现可用于仅符合资格的 LUAD 人群的个性化疗法 常规化疗。

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.