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（Warburg效应）被认为允许更快的能量生产速率，以及作为支持肿瘤细胞苛刻生长需要的构建块所需的分子的产生。尽管包括c-myc和PI3K在内的几个致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，这导致我们对癌症代谢机制方面的知识存在重大差距，并限制了我们利用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

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.