Matrix Stiffness Modulates Metabolic Interaction Between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

Abstract Background. Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work is to investigate the possible functional link among these two processes.Methods. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material to which matrix molecules were covalently-linked. We evaluated metabolite transport in stromal cells using two different FRET nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices.Results. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner.Conclusions. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote the metabolic reprograming that also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming and cancer malignancy.