Molecular Characterization of Autophagy in Salivary Gland Tumors

唾液腺肿瘤自噬的分子特征

• 批准号: 8572902
• 负责人: David K Ann
• 金额: $ 23.1万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8572902
• 关键词: Address; Affect; Animal Model; Autophagocytosis; Biological Assay; Cancer Etiology; Carcinoma; Catabolic Process; Cell Lineage; Cell Proliferation; Cell Survival; Cells; Chromosomal Instability; Clinical; Clinical Trials; Coin; Colon; Cytoplasmic Organelle; Cytoplasmic Protein; DNA Damage; DNA Double Strand Break; Data; Development; Diagnosis; Eating; Energy-Generating Resources; Essential Genes; Event; Evolution; Failure; Functional disorder; Future; Genetic; Genetic Transcription; Genome Stability; Glare; Glutamine; Glycolysis; Goals; Growth; HRAS gene; Heterogeneity; Histopathology; Homeostasis; Human; Investigation; Knock-out; Knowledge; Label; Link; Lung; Lysosomes; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of salivary gland; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Mitochondria; Molecular; Molecular Profiling; Mus; Mutation; Normal Cell; Normal tissue morphology; Nucleotides; Oncogenic; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Pancreas; Pathway interactions; Play; Population; Prevention; Process; Publishing; Reactive Oxygen Species; Regulation; Reporting; Role; Salivary; Salivary Gland Neoplasms; Salivary Glands; Signal Pathway; Staging; Stress; Submandibular Gland Neoplasms; Submandibular gland; System; Tamoxifen; Testing; Therapeutic; Time; Tissues; Transgenes; Transgenic Mice; Transgenic Model; Tumor Expansion; Tumor Promotion; Tumor Suppressor Proteins; Tumor Tissue; Validation; Warburg Effect; anaerobic glycolysis; base; cancer cell; cancer therapy; cell growth; cell type; experience; feeding; in vivo; innovation; mouse model; mutant; neoplastic cell; new therapeutic target; novel; pre-clinical; public health relevance; recombinase; therapeutic target; tool; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this project is to elucidate how autophagy regulates the onset and progression of salivary gland tumors, and how the pathway interacts with oncogenic signaling pathways during tumorigenesis. Salivary gland tumors are both rare and highly varied. Because of their rarity, previous investigation of salivary cancer is limited an as yet, there are no useful mouse models of salivary gland cancer available that resemble the pathophysiology of human salivary cancers. Consequently, therapeutic options for salivary tumors are limited, personalized treatment is virtually non-existent and there is a glaring lack of pre-clinical and clinical validation. Autophagy is a catabolic process that uses the cell's lysosomal system to degrade its own components including cytoplasmic organelles and proteins. In the last decade, it has been established that autophagy plays important and complicated roles in the onset and progression of tumors via multiple mechanisms. It is therefore a promising therapeutic target and nearly 20 clinical trials targeting autophagy are in progress. Although autophagy promotes tumor progression in later stages, it plays a tumor-suppressive role early during tumorigenesis. Therefore it is crucial to determine the precise role of autophagy at different stages of salivary tumor development for future autophagy-based therapeutics. The role of autophagy is not well studied in salivary tumors, but our preliminary data, together with published reports, indicate that autophagy plays a "dual role." It reduces genetic instability early during tumorigenesis to suppress tumor formation, but then shifts its rol to provide a survival advantage for established tumors experiencing endogenous and exogenous metabolic stresses. We hypothesize that autophagy suppresses tumor initiation by inhibiting the formation of tumor-initiating cells, but acts as a key metabolic pathway for the survival of advanced salivary tumors. We will determine the role autophagy plays in suppressing submandibular tumorigenesis using a mouse model that contains a K-RasG12V transgene. The K-RasG12V can be activated to specifically induce tumors in submandibular tissue, using a Cre-recombinase that is induced by tamoxifen-feeding. We will knock-out Atg5, an essential gene for autophagy, to impair autophagy in the K-RasG12V background. Using nucleotide labeling to trace cell lineages, we will compare specific sub-populations of salivary tumor cells from autophagy- competent and autophagy-impaired K-RasG12V transgenic mice. The novel transgenic mouse model developed for this proposal will not only assist us in understanding the role of autophagy in regulating salivary tumorigenesis, but will also be invaluable as tools to screen for, and identify, novel therapeutic targets to treat these rare, but deadly cancers. Furthermore, the new knowledge will have potential relevance to the role of autophagy in regulating other oncogenic Ras-induced cancers.

项目描述（由申请人提供）：本项目旨在阐明自噬如何调节唾液腺肿瘤的发生和发展，以及该途径在肿瘤发生过程中如何与致癌信号通路相互作用。唾液腺肿瘤既罕见又多种多样。由于其罕见性，以往对唾液腺癌的研究是有限的，到目前为止，还没有类似于人类唾液腺癌病理生理的有用的小鼠唾液腺癌模型。因此，唾液腺肿瘤的治疗选择是有限的，个性化治疗实际上是不存在的，而且明显缺乏