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 最终治疗功效是人类的主题，但需要更详细的信息 适当的更好控制模型。我们已经开始了稳定的同位素解析代谢组学（SIRM） 接受手术切除的患者的非小细胞肺癌（NSCLC）的研究。在我们的飞行员中 研究我们利用了匹配的恶性和良性肺组织的固有力量以及 在手术前使用“ C标记的葡萄糖给予IV的葡萄糖，以绘制原位的细胞内代谢途径 第一次。这导致发现线粒体丙酮酸羧化酶（PCB）被激活为 补充肿瘤中生物合成所需的克雷布斯循环中间体。这是进一步的 与配对相比 良性肺组织以及通过PCB敲除对NSCLC细胞的生长抑制。对 这些研究的解释是我们获得的有关细胞培养的其他详细信息，以及 小鼠模型，该模型提供了在肿瘤组织中寻找的代谢特征。）。我们的初步 发现还表明，肺部肿瘤中还有更多的代谢区别。基础 途径和法规尚未定义。我们现在寻求将方法扩展到更大的队列 NSCLC并添加了一种新的Ex Vivo“ Warburg”组织切片方法，以更好地定义大规模定义 NSCLC中的代谢重编程，具有流行的驱动基因缺陷。这些直接的人类研究将是 与模型细胞（项目1）和动物研究（项目2）并行进行，以促进解释。 我们还将采用这种综合方法来探索肿瘤回归的代谢机制 β-葡聚糖术前治疗的影响。我们假设这种影响可能部分是 由β-葡聚糖激活居民巨噬细胞中葡萄糖和杜松子代谢的激活，这是一种关键的免疫 根据我们的最新数据和文献，肿瘤微环境中的调节剂（参见项目2）。 我们将进一步探索通过脂质的肺肿瘤组织与血浆代谢的联系 微泡（MV），已知通过具有转移能力的肺癌细胞释放。我们有 新的证据表明，血浆MV的脂质特征在肺和乳腺癌的早期阶段与众不同 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MV代谢特征的未来 应用为临床指标。这些目标将通过三个特定目标实现。