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 developmentof 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 ourknowledge 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.