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.
It is now widely recognized that many cancer cells change the way they produce energy and metabolize glucose, a phenomenon known as the Warburg effect. While some of the mechanisms leading to this metabolic reprogramming have been elucidated, they account for only a fraction of the complex network of signals and pathways governing energy metabolism. The Warburg effect is considered one of the hallmarks of cancer cells and has already found clinical application, since it represents the rationale for PET imaging. Thyroid cancer, one of the few cancer types showing an increase in incidence, shares this hallmark. Our laboratory has recently found that thyroid tumors developing in mice carrying a mutation often found in human tumors, display the Warburg effect. However, not only this metabolic change takes place well before a recognizable tumor has developed, but it is achieved through a mechanism completely different from the ones so far identified in other models. In this project, we will define in detail the molecular mechanisms responsible for this type of Warburg effect, and generate knowledge that will lead to innovative, targeted approaches to selectively disrupt tumor growth, while preserving normal metabolism in non mutated cells.
