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

基本信息

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
项目类别：
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

项目摘要

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、肿瘤进展和肿瘤之间关系的金标准最终的治疗效果取决于人类受试者，但需要更详细的信息适当的更好的控制模型。我们已经开始稳定同位素解析代谢组学 (SIRM) 对接受手术切除的非小细胞肺癌（NSCLC）患者进行的研究。在我们的试点中我们的研究利用了配对的恶性和良性肺组织的固有力量以及使用“手术前静脉注射C标记的葡萄糖来绘制原位细胞内代谢途径第一次。这导致了线粒体丙酮酸羧化酶（PCB）被激活的发现补充肿瘤生物合成（即回补）所需的克雷布斯循环中间体。这进一步与配对相比，肿瘤中 PCB 的 mRNA 和蛋白表达增加证实了这一点良性肺组织，以及通过 PCB 敲低抑制 NSCLC 细胞的生长。对这些研究的解释是我们获得的有关细胞培养的额外详细信息，以及小鼠模型，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，肺部肿瘤存在更多代谢差异。底层的途径和监管尚未确定。我们现在寻求将这种方法扩展到更多的群体 NSCLC 并添加了新的离体“Warburg”组织切片方法，以更好地大规模定义具有普遍驱动基因缺陷的非小细胞肺癌的代谢重编程。这些直接的人体研究将与模型细胞（项目 1）和动物研究（项目 2）同时进行，以促进解释。我们还将应用这种综合方法来探索肿瘤消退的代谢机制 β-葡聚糖术前治疗的效果。我们假设这种影响可能部分是由于由β-葡聚糖激活常驻巨噬细胞中的葡萄糖和杜松子酒代谢介导，这是一种关键的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）。我们将进一步探讨肺肿瘤组织通过脂质代谢与血浆代谢的联系。微泡（MV），已知由肺癌细胞释放，具有促进转移的能力。我们有新证据表明血浆MV的脂质谱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未来的 MV 代谢特征作为临床指标的应用。这些目标将通过三个具体目标来实现。