PI3K-mediated metabolic alterations in the pre-neoplastic thyroid

PI3K介导的肿瘤前甲状腺代谢改变

• 批准号: 8600660
• 负责人: Antonio Di Cristofano
• 金额: $ 33.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600660
• 关键词: Accounting; Biochemical Pathway; Biological Models; Candidate Disease Gene; Carcinoma; Catabolism; Cells; Citric Acid Cycle; Clinical; Complex; Consumption; DNA Sequence Rearrangement; Development; Down-Regulation; Energy Metabolism; Ensure; Enzymes; Epithelial; Epithelial Cells; Gene Expression; Gene Expression Profile; Generations; Genes; Glucose; Glycolysis; Goals; Growth; Human; Hyperplasia; Hypoxia; Incidence; Knowledge; Laboratories; Lead; Lesion; Malignant neoplasm of thyroid; Mediating; Membrane; Metabolic; Metabolism; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutate; Mutation; Neoplastic Cell Transformation; Normal Cell; Nucleic Acids; Oncogene Deregulation; Oncogenes; Oxidative Phosphorylation; Oxygen; Pathway interactions; Positron-Emission Tomography; Process; Production; Protein Biosynthesis; Proteome; Proto-Oncogene Proteins c-akt; Relative (related person); Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Thyroid Gland; Tricarboxylic Acids; Warburg Effect; aerobic glycolysis; base; c-myc Genes; cancer cell; cancer type; cell transformation; clinical application; clinically relevant; driving force; fasting glucose; glucose uptake; in vivo; in vivo Model; innovation; mutant; neoplastic; neoplastic cell; novel; public health relevance; respiratory; thyroid neoplasm; tumor; tumor growth; tumor initiation; tumor metabolism; tumor microenvironment; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Most cancer cells produce energy by aerobic glycolysis instead of oxidative phosphorylation. This metabolic switch (Warburg effect) is thought to allow a faster energy production rate as well as the generation of molecules needed as building blocks to support the demanding growth needs of a tumor cell. Although several oncogenes, including c-myc and PI3K, have been causally associated with this shift, our understanding of how metabolism is rewired is still largely incomplete, resulting in a major gap in our knowledge of the mechanistic aspects of cancer metabolism, and limiting our ability to harness these changes for clinical purposes. We have generated a mouse strain in which the PI3K pathway is selectively activated in the thyroid epithelial cells, resulting in the development of hyperplasia and, later, carcinoma. This mouse strain represents a physiologically and clinically relevant system to study epithelial neoplastic transformation and tumor progression. By interrogating the thyroid proteome and transcriptome, we have found that the expression of most genes involved in the tricarboxylic acid (TCA) cycle and in the oxidative phosphorylation process is drastically reduced in the hyperplastic lesions developing in young mutant mice. This down-regulation is accompanied by a strikingly enhanced glycolytic rate. This novel, pre-neoplastic, version of the Warburg effect is not associated with activation of any of the pathways classically involved in the metabolic reprogramming of highly proliferative and transformed cells, and is maintained when the hyperplastic lesions progress to follicular and poorly differentiated carcinomas. Based on these compelling findings, we propose to test the hypothesis that PI3K activation initiates a coordinated rearrangement of metabolic gene expression, favoring aerobic glycolysis at the expense of TCA/OXPHOS, and promotes a metabolic landscape supporting neoplastic transformation. The elucidation of this novel pathway will fill a significant gap in our knowledge of the mechanisms responsible for the metabolic changes associated with early neoplastic transformation, and will contribute to develop innovative targeted approaches to selectively disrupt tumor growth, while preserving regular metabolism in normal cells.

描述(申请人提供)：大多数癌细胞通过有氧糖酵解而不是氧化磷酸化来产生能量。这种代谢开关(Warburg效应)被认为允许更快的能量产生速度，以及产生作为构建块的分子，以支持肿瘤细胞苛刻的生长需求。尽管包括c-myc和PI3K在内的几个癌基因与这种转变有因果关系，但我们对新陈代谢如何重新连接的了解仍然很不完整，导致我们对癌症新陈代谢机制方面的知识存在重大差距，并限制了我们将这些变化用于临床目的的能力。我们已经产生了一种小鼠品系，其中PI3K通路在甲状腺上皮细胞中被选择性激活，导致发育 增生性疾病，后来是癌症。这种小鼠品系代表了一种生理和临床上相关的系统，用于研究上皮肿瘤转化和肿瘤进展。通过询问甲状腺蛋白质组和转录组，我们发现在年轻突变小鼠的增生性病变中，参与三羧酸(TCA)循环和氧化磷酸化过程的大多数基因的表达显著减少。这种下调伴随着糖酵解率的显著提高。这一新颖的肿瘤前版本的Warburg效应与任何经典的参与高增殖和转化细胞代谢重编程的途径的激活无关，并在增生性病变进展为滤泡性和低分化癌时保持不变。基于这些令人信服的发现，我们建议检验以下假设：PI3K激活启动代谢基因表达的协调重排，以TCA/OXPHOS为代价促进有氧糖酵解，并促进支持肿瘤转化的代谢格局。这一新途径的阐明将填补我们在 了解与早期肿瘤转化相关的代谢变化的机制，并将有助于开发有针对性的创新方法，选择性地破坏肿瘤生长，同时保持正常细胞的正常代谢。