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，也是肺癌的主要原因。 对于大量 LUAD 患者来说，这是唯一的治疗选择。 对于这些患者，可用的是传统的多药化疗结合手术和/或放疗。 令人失望的是，驱动 LUAD 增殖的其他分子机制仍然很低。 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 最近的报告（包括我们自己的报告）揭示了糖原在治疗中的关键作用。 在这些基础研究的基础上，我们开发了稳健且精确的方法。 使用质谱成像以 50 µm 空间分辨率原位可视化糖原的技术 我们定义，与以前的方法相比，使用该技术的灵敏度提高了 1,000 倍。 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 中观察到糖原升高，而在 2) 糖原升高是 LUAD 组织特异性标志，在肺组织中未观察到。 3) LUAD-糖原结构独特，磷酸化程度增加。 4) 这种 LUAD 表型与糖原磷酸酶中蛋白质的显着减少相关。 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。 我们勇敢地承认结构独特的 LUAD 糖原是 LUAD 代谢的关键组成部分， 本研究的总体目标是确定 LUAD-糖原的病因学。 为了实现这一目标，我们将： 定义 LUAD 糖原临床。 然后，我们将定义 LUAD-糖原在其中的信号传导作用。 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。 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糖原过度利用的独特 LUAD 标志 稳健、互补且最先进的方法，例如质谱成像、蛋白质和 该提案的显着发现将显着影响糖原生物化学和靶向代谢组学。 推进关于糖原在 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。