PI3K-mediated metabolic alterations in the pre-neoplastic thyroid

描述（由申请人提供）：大多数癌细胞通过有氧糖酵解而不是氧化磷酸化产生能量。这种代谢开关（瓦尔堡效应）被认为允许更快的能量产生速率以及作为构建模块所需的分子的产生，以支持肿瘤细胞苛刻的生长需求。尽管包括c-myc和PI 3 K在内的几种癌基因与这种转变有因果关系，但我们对代谢如何重新连接的理解在很大程度上仍然不完整，导致我们对癌症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PI 3 K通路在甲状腺上皮细胞中选择性激活，导致甲状腺上皮细胞的发育。 然后是癌。该小鼠品系代表了研究上皮肿瘤转化和肿瘤进展的生理学和临床相关系统。通过询问甲状腺蛋白质组和转录组，我们已经发现，参与三羧酸（TCA）循环和氧化磷酸化过程中的大多数基因的表达急剧减少，在年轻的突变小鼠的增生性病变发展。这种下调伴随着显著增强的糖酵解速率。这种新的肿瘤前版本的瓦尔堡效应与高度增殖和转化细胞的代谢重编程中经典参与的任何途径的激活无关，并且在增生性病变进展为滤泡和低分化癌时维持。基于这些令人信服的研究结果，我们建议测试的假设，PI 3 K激活启动代谢基因表达的协调重排，有利于有氧糖酵解的TCA/OXPHOS的代价，并促进支持肿瘤转化的代谢景观。这一新途径的阐明将填补我们在这方面的一个重大空白。 这将有助于了解负责与早期肿瘤转化相关的代谢变化的机制，并将有助于开发创新的靶向方法，以选择性地破坏肿瘤生长，同时保持正常细胞的正常代谢。

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.