Extensive studies of recent years reveal additional layers of complexity that characterize cancer cells. This complexity includes the understanding that tumors exhibit different aspects of cellular metabolism relative to non-proliferative normal cells, as they need to support the cell replication machinery. However, cancer-dependent metabolic rewiring revealed to be more complicated as initially described since metabolic processes that are essential only to a particular type of tumors had recently been characterized. These findings imply that the demand for metabolic rewiring in promoting malignancy is not limited to support cell replication but may also be required to serve other cellular processes. 

The epithelial-mesenchymal transition (EMT) program was initially described as an early developmental program used by epithelial cells to trans-differentiate and gain mesenchymal-like properties. Execution of this program induces significant morphological changes, resulting in cell-cell junctions release and loss of cell polarity. Similar properties were later detected in tumors and suggested the EMT program as the mechanism by which carcinomas gain the ability to metastasize, become chemoresistance, and generates cancer stem cells. The EMT complex regulation indicates a balance between the signals that induce trans-differentiation and those that suppress it.

The goal of our lab is to characterize novel cellular processes that regulate tumor progression. Specifically, we aim to identify these metabolic genes that regulate the EMT program and understand their mechanisms of action.

To identify the metabolic genes that regulate tumor progression, we previously created a bioinformatic-based framework (Metabolic gEne RApid Visualizer (MERAV, http://merav.wi.mit.edu) for the systematic identification of metabolic alterations specific to particular tumor types. This analysis yields the identification of 44 metabolic genes present in high-grade tumors bearing mesenchymal markers, which we designated as "mesenchymal metabolic signature" (MMS). Among them is dihydropyrimidine dehydrogenase (DPYD), the pyrimidine degradation pathway rate-limiting enzyme, and glutathione peroxide 8 (GPX8) that we further validated their role in tumor aggressiveness. Our rationale is that the more we know of the metabolites involved in tumor progression, the better we uncover novel mechanisms essential for this process.