Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells

Cancer and other cells residing in the same niche engage various modes of interactions to synchronize and to buffer the negative effects of environmental changes. Extracellular miRNAs have been recently implicated in the intercellular crosstalk. Here we show a mechanistic model involving breast-cancer-secreted, extracellular-vesicle-encapsulated miR-105, which is induced by the oncoprotein MYC in cancer cells and in turn activates MYC signaling in cancer-associated fibroblasts (CAFs) to induce a metabolic program. This results in CAFs’ capacity to display different metabolic features in response to changes in the metabolic environment. When nutrients are sufficient, miR-105-reprogrammed CAFs enhance glucose and glutamine metabolism to fuel adjacent cancer cells. When nutrients are deprived whereas metabolic byproducts are accumulated, these CAFs detoxify metabolic wastes, including lactic acid and ammonium, by converting them into energy-rich metabolites. Thus, the miR-105-mediated metabolic reprogramming of stromal cells contributes to sustained tumour growth by conditioning the shared metabolic environment.