Determining Molecular Mechanisms of NSCLC and Response to beta-glucan

确定 NSCLC 的分子机制和对 β-葡聚糖的反应

• 批准号: 8744924
• 负责人: Teresa Whei-Mei Fan
• 金额: $ 25.7万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-19 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8744924
• 关键词: Adenocarcinoma; Age; Anabolism; Animals; Benign; Biochemical; Biochemistry; Cancer Patient; Cell Culture Techniques; Cell model; Cells; Cessation of life; Characteristics; Citric Acid Cycle; Clinical; Coupled; Data; Defect; Diagnostic Neoplasm Staging; Early Diagnosis; Excision; Future; Gene Expression Profile; Genes; Glucose; Glutamine; Goals; Gold; Growth; Human; Immune; Immune response; In Situ; Infusion procedures; Instruction; Knowledge; Label; Learning; Link; Lipids; Literature; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; North America; Oncogenes; Oncogenic; Operative Surgical Procedures; Outcome; Pathological Staging; Pathway interactions; Patients; Pilot Projects; Plasma; Pyruvate Carboxylase; Recruitment Activity; Regulation; Resected; Sample Size; Sampling; Slice; Squamous cell carcinoma; Staging; Structure of parenchyma of lung; System; Testing; Therapeutic; Time; Tissues; Tracer; Treatment Efficacy; Tumor Subtype; Tumor Tissue; Tumor stage; base; beta-Glucans; cancer cell; cohort; design; human subject; improved; mRNA Expression; macrophage; malignant breast neoplasm; metabolomics; mouse model; novel diagnostics; novel strategies; outcome forecast; protein expression; response; stable isotope; tumor; tumor metabolism; tumor microenvironment; tumor progression

The gold standard for understanding the connection between tumor metabolism, tumor progression and ultimately therapeutic efficacy is the human subject, but more detailed information is needed from appropriate better controlled models. We have begun a Stable Isotope Resolved Metabolomics (SIRM) study of non-small cell lung cancer (NSCLC) from patients who underwent surgical resection. In our pilot study we capitalized on the inherent power of the matched pairs of malignant and benign lung tissue and the use of "C-labeled glucose administered iv prior to surgery to map in situ intracellular metabolic pathways for the first time. This led to the discovery that mitochondrial pyruvate carboxylase (PCB) is activated to replenish Krebs cycle intermediates required for biosynthesis (i.e. anaplerosis) in tumors. This was further corroborated by increased mRNA and protein expression of PCB in the tumors compared with the paired benign lung tissue, as well as growth inhibition of NSCLC cells by PCB knockdown. Critical to the interpretation of these studies was the additional detailed information that we obtained on cell culture, and mouse models, which provided metabolic signatures to look for in the tumor tissue.). Our preliminary findings also indicate that there are many more metabolic distinctions in lung tumors; the underlying pathways and regulation have yet to be defined. We now seek to extend the approach to a larger cohort of NSCLC and added a new ex vivo "Warburg" tissue slice approach to better define in large-scale the metabolic reprogrammings in NSCLC with prevailing driver gene defects. These direct human studies will be conducted in parallel with model cell (Project 1) and animal studies (Project 2) to facilitate interpretation. We will also apply this integrated approach to explore the metabolic mechanism underlying the tumor-regressive effect of a pre-operative treatment with beta-glucans. We hypothesize that this effect may be in part mediated by beta-glucan's activation of glucose and Gin metabolism in resident macrophages, a key immune modulator in the tumor microenvironment, based on our most recent data and the literature (cf. Project 2). We will further explore the linkage of lung tumor tissue to blood plasma metabolism via the lipidic microvesicles (MV), known to be released by lung cancer cells with metastasis-promoting capacity. We have new evidence that the lipid profile of plasma MV is distinct among early stages of lung and breast cancer patients and healthy subjects. We will test if beta-glucan treatment can alter MV metabolic signatures for future application as clinical indicators. These goals will be achieved via the three specific aims.

了解肿瘤代谢、肿瘤进展和肿瘤进展之间关系的黄金标准 最终的治疗效果是人类的主题，但更详细的信息需要从 适当的更好控制的模型。我们已经开始了稳定同位素分解代谢组学(SIRM) 手术切除非小细胞肺癌(NSCLC)的研究在我们的试点中 研究中，我们利用了配对的恶性和良性肺组织的内在力量，以及 术前静脉注射“C-标记葡萄糖”原位标测细胞内代谢途径 第一次。这导致发现线粒体丙酮酸羧基酶(PCB)被激活以 补充肿瘤生物合成(即再生)所需的Krebs循环中间体。这是更远的 与配对的肿瘤相比，肿瘤中PCBmRNA和蛋白的表达增加证实了这一点 良性肺组织，以及印刷电路板击倒对非小细胞肺癌细胞生长的抑制。对美国的 对这些研究的解释是我们获得的关于细胞培养的额外详细信息，以及 老鼠模型，它提供了要在肿瘤组织中寻找的代谢信号。)我们的预赛 研究结果还表明，在肺部肿瘤中有更多的代谢差异；潜在的 途径和监管尚未确定。我们现在寻求将这一方法扩展到更大范围的 NSCLC并增加了一种新的体外“Warburg”组织切片方法，以更好地在大规模 普遍存在驱动基因缺陷的非小细胞肺癌患者的代谢重编程。这些直接的人体研究将是 与模型细胞(项目1)和动物研究(项目2)并行进行，以便于解释。 我们还将应用这种综合方法来探索肿瘤退行性变背后的代谢机制。 术前应用β-葡聚糖治疗的效果。我们推测，这种影响可能部分是 由β-葡聚糖激活驻留巨噬细胞葡萄糖和Gin代谢介导的关键免疫 肿瘤微环境中的调节剂，基于我们最新的数据和文献(参见。项目2)。 我们将通过脂类进一步探讨肺癌组织与血浆代谢的联系。 微泡(MV)，已知是由具有促进转移能力的肺癌细胞释放的。我们有 肺癌和乳腺癌早期患者血浆MV脂谱不同的新证据 患者和健康受试者。我们将测试β-葡聚糖治疗是否可以改变未来MV的代谢特征 作为临床指标应用。这些目标将通过三个具体目标来实现。