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Metabolic reprogramming and tumor progression in LKB1 deficient NSCLC

LKB1 缺陷型 NSCLC 的代谢重编程和肿瘤进展

基本信息

批准号：
10477469
负责人：
Austin C Boese
金额：
$ 4.68万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477469
关键词：
Adenocarcinoma Anoikis Antioxidants Apoptotic Bioenergetics Biogenesis Bioinformatics Biological Markers Blood Vessels Cancer Etiology Cancer Patient Cancer cell line Cardiovascular system Cell Death Cell Survival Cells Cessation of life Characteristics Clinical Clinical Management Complex Custom Data Diagnosis Disseminated Malignant Neoplasm Distant Drug Targeting Enzymes Equilibrium Exhibits Extracellular Matrix Fellowship Future Genes Genetic Glutamate Dehydrogenase Goals Homeostasis Immune Evasion Immune checkpoint inhibitor Immunohistochemistry Immunotherapy In Vitro Laboratories Large Cell Carcinoma Link Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Molecular Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nonmetastatic Nutrient Organ Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Patient-Focused Outcomes Patients Phenotype Play Primary Neoplasm Process Production Proteins RNA interference screen Reactive Oxygen Species Reporting Research Research Personnel Research Proposals Resistance Role STK11 gene Signal Transduction Squamous cell carcinoma Stains Succinate-CoA Ligases Supplementation Testing Tissues Training Tumor Escape United States Uric Acid Warburg Effect aerobic glycolysis cancer cell cancer therapy career checkpoint therapy combat experimental study improved in vivo inhibitor knock-down lung cancer cell lymphatic vessel mRNA Expression metabolic phenotype metabolic profile metabolomics mortality neoplastic cell novel pre-doctoral preclinical efficacy preference programs response targeted biomarker therapeutic target therapy resistant tumor tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY Dysregulated cellular metabolism is a common characteristic of cancer, but a growing body of research highlights significant differences in metabolic phenotypes both within primary tumors, and in tumor cells that metastasize to distant organs. While highly proliferative primary tumor cells often exhibit the Warburg effect, marked by a preference for aerobic glycolysis to generate ATP, genes for mitochondrial biogenesis and oxidative phosphorylation are reported to be upregulated in metastatic cancer cells. Therefore, detailed characterization of reprogrammed metabolic pathways in lung cancer may reveal useful targets to combat tumor progression and improve patient survival. In order to metastasize, cancer cells must first resist anoikis: an apoptotic cell death mechanism triggered by loss of proper contact with the extracellular matrix. Our lab has previously demonstrated that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) contributes to anoikis resistance and metastasis by regulating the bioenergetic response through reactivation of AMPK in LKB1-deficient lung cancer. However, the role of other mitochondrial enzymes in anoikis resistance remains poorly understood. To identify other factors important for cancer cell anoikis resistance, we performed an unbiased RNAi screen targeting 120 mitochondrial enzymes in lung cancer cells and identified the ATP- specific Succinyl-CoA Synthetase beta subunit (SUCLA2) as a factor that may be important for cancer cell survival after ECM detachment. Stable knockdown of SUCLA2 sensitized lung cancer cell lines to anoikis when cultured under non-adherent conditions in vitro. Bioinformatic analysis of publicly available data indicates that higher tumor SUCLA2 mRNA expression is associated with poor patient survival, and our immunohistochemistry staining suggests that SUCLA2 protein levels are higher in metastatic lung cancer compared to matched primary tumors. Additionally, our data suggests that SUCLA2 knockdown significantly increases reactive oxygen species (ROS) production and anoikis sensitivity in ECM detached cancer cells, which can be reversed with antioxidant NAC supplementation. In the first half of this research proposal, we will employ multiple approaches to decipher how SUCLA2 modulates cellular redox status to promote anoikis resistance and tumor metastasis. The second half of the proposal lays out a plan for a productive postdoctoral fellowship (K00) that will build on applicant's predoctoral F99 training and prepare him well to start a career as an independent cancer researcher.

项目总结