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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.

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