Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis

肺腺癌肿瘤发生中的异常糖原

• 批准号: 10518440
• 负责人: Matthew S. Gentry
• 金额: $ 5.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10518440
• 关键词: 5' -AMP-activated protein kinase; Affinity; Apoptosis; Automobile Driving; Binding; Biochemical; Biochemistry; Biological Assay; Biology; Biophysics; Cancer Biology; Cancer Etiology; Cancer Patient; Carbon; Cell Cycle; Cell Line; Clinical; Coupled; Data; Development; Diagnosis; Etiology; Foundations; Future; Genetic; Glucose; Glycogen; Goals; Histologic; In Situ; KRASG12D; Kentucky; Knock-out; Knowledge; Lipids; Longitudinal Studies; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Metastatic Neoplasm to Lymph Nodes; Methodology; Methods; Modality; Modeling; Molecular; Monitor; Mus; Mutate; Mutation; NCI-Designated Cancer Center; Non-Small-Cell Lung Carcinoma; Nucleotides; Oncogenic; Operative Surgical Procedures; Organoids; Pathogenicity; Patients; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Population; Precision therapeutics; Property; Protein Kinase; Proteins; Quality of life; Radiation; Reporting; Resolution; Role; STK11 gene; Sampling; Signal Transduction; Squamous Cell Lung Carcinoma; Staging; Structure of parenchyma of lung; TP53 gene; Technology; Testing; Tissues; Transgenic Mice; Tumor Biology; Tumor Pathology; Universities; anticancer research; base; chemotherapy; cohort; fatty acid oxidation; genetically modified cells; glucose metabolism; in vivo; knowledge base; mass spectrometric imaging; metabolomics; mortality; mouse model; mutant; novel; personalized medicine; pre-clinical; prevent; stable isotope; tumor; tumor metabolism; tumor progression; 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.

摘要： 肺腺癌（LUAD）是肺癌的主要组织学亚型，也是导致肺癌的主要原因。 全球癌症相关死亡率。对于大量LUAD患者，唯一的治疗选择 可用的是与手术和/或放射结合的传统多药剂化学疗法。对于这些患者， 5年生存率仍然低得令人不安。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关键知识差距，也是肺癌研究的主要障碍。 个性化治疗的发展。最近的报告，包括我们自己的报告，揭示了糖原在 肺部肿瘤进展。在这些基础研究的基础上，我们开发了一种强大而精确的 利用质谱成像技术，以50 µm的空间分辨率原位显示糖原， 与以前的方法相比，灵敏度提高了1，000倍。利用这项技术，我们定义了 在肯塔基州大学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中观察到显著升高的糖原，而在 正常的肺组织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-糖原在结构上是独特的，磷酸化增加， 分支4)这种LUAD表型与糖原磷酸酶的蛋白质显著减少相关 拉福林引人注目的是，模型肺细胞系和KrasG 12 D/p53-/- LUAD小鼠模型中的laforin敲除驱动：1） 糖原过度磷酸化，2）与主代谢调节因子AMP激活的亲和力增加 蛋白激酶（AMPK），3）降低AMPK活性，和4）加速肿瘤增殖和进展。 我们假设结构独特的LUAD-糖原是LUAD代谢的关键组分， 增殖和进展。本研究的总体目标是确定LUAD-糖原的病因， 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 过程及其与AMPK的相互作用（目的1）。然后，我们将定义LUAD-糖原的信号传导作用， 通过AMPK的细胞代谢（目的2）。最后，我们将建立LUAD-糖原在肿瘤中的作用 进展和体内早期转化（Aim 3）。该提案建立在令人兴奋和严格的初步 数据，并提出了一个综合的方法来定义这种独特的LUAD标志，过量的糖原利用 强大的，互补的，最先进的方法，如质谱成像，蛋白质和 糖原生物化学和靶向代谢组学。该提案的主要结论将大大 推进关于糖原在LUAD生物学和进展中的作用的知识基础，并推动 发现可用于仅符合以下条件的LUAD人群的个性化疗法： 常规化疗。