Cancer cell metabolism regulates extracellular matrix degradation by invadopodia.

Transformed cancer cells have an altered metabolism, characterized by a shift towards aerobic glycolysis, referred to as 'the Warburg phenotype'. A change in flux through mitochondrial OXPHOS and cytosolic pathways for ATP production and a gain of capacity for biomass production in order to sustain the needs for altered growth and morphodynamics are typically involved in this global rewiring of cancer cell metabolism. Characteristically, these changes in metabolism are accompanied by enhanced uptake of nutrients like glucose and glutamine. Here we focus on the relationship between cell metabolism and cell dynamics, in particular the formation and function of invadopodia, specialized structures for focal degradation of the extracellular matrix. Since we recently found presence of enzymes that are active in glycolysis and associated pathways in invadopodia, we hypothesize that metabolic adaptation and invadopodia formation are linked processes. We give an overview on the background for this idea and show for the first time that extracellular matrix degradation by invadopodia can be differentially manipulated, without effects on cell proliferation, by use of metabolic inhibitors or changes in nutrient composition of cell culture media. We conclude that cell metabolism and carbohydrate availability, especially pyruvate, are involved in fuelling of invadopodia formation and activity.