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、肿瘤进展和肿瘤转移之间联系的金标准是： 最终的治疗效果是人类受试者，但需要更详细的信息， 更好的控制模式。稳定同位素解析代谢组学（Stable Isotope Resolved Metabolomics，SIRM） 非小细胞肺癌（NSCLC）患者接受手术切除的研究。在我们的试播集里 我们的研究利用了恶性和良性肺组织配对的内在力量， 使用在手术前静脉内给予的“C-标记的葡萄糖”来原位绘制细胞内代谢途径， 第一次这导致发现线粒体丙酮酸羧化酶（PCB）被激活， 补充肿瘤中生物合成（即回补）所需的克雷布斯循环中间体。这进一步 与对照组相比，肿瘤中PCB的mRNA和蛋白表达增加， 良性肺组织，以及通过PCB敲除抑制NSCLC细胞的生长。的关键 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， 小鼠模型，其提供了在肿瘤组织中寻找的代谢特征。我们的初步 研究结果还表明，在肺肿瘤中有更多的代谢差异; 路径和监管尚待确定。我们现在寻求将这种方法扩展到更大的群体， NSCLC，并增加了一种新的离体“瓦尔堡”组织切片方法，以更好地在大规模中定义 代谢重编程的非小细胞肺癌与普遍的驱动基因缺陷。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）平行进行，以便于解释。 我们还将应用这种综合方法来探索肿瘤消退的代谢机制 术前β-葡聚糖治疗的效果。我们推测，这种影响可能部分是由于 通过β-葡聚糖激活常驻巨噬细胞中的葡萄糖和Gin代谢介导，巨噬细胞是一种关键的免疫系统， 调节剂在肿瘤微环境中的作用，基于我们最新的数据和文献（cf.项目2）。 我们将进一步探讨肺肿瘤组织与血浆代谢的联系， 微囊泡（MV），已知由具有转移促进能力的肺癌细胞释放。我们有 新的证据表明，血浆MV的脂质分布在肺癌和乳腺癌的早期阶段是不同的 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， 作为临床指标。这些目标将通过三个具体目标来实现。