Cancer cells have a high and unique metabolic demand, and thus it is of interest to gain insights into the mechanisms that govern nutrient uptake. Overexpression of oncogenic Ras is known to stimulate macropinocytosis, an endocytic process whereby cells internalize extracellular fluid and its contents. Bar-Sagi and colleagues (Nature 497, 633–637; 2013) have now demonstrated the functional importance of this process in Ras-transformed cancer cells. By studying these cells both in vitro and in vivo, the authors showed that they displayed increased levels of macropinocytosis, which enhanced albumin internalization and subsequently increased intracellular levels of glutamine and its downstream metabolite α-ketoglutarate. Furthermore, catabolized proteins entered the central metabolism, and protein-derived amino acids were metabolized through several pathways. The increased level of macropinocytosis translated into an increased proliferation of cells deprived of glutamine but supplemented with albumin. Increased protein uptake and proliferation could also be generalized to cells with enhanced levels of macropinocytosis regardless of Ras status. Interestingly, in mice, inhibition of macropinocytosis using a specific inhibitor of macropinosome formation resulted in attenuation or regression of tumour growth.

This shows that in cancer cells, increased levels of macropinocytosis can be a beneficial nutrient uptake mechanism to support proliferation. Therefore, inhibiting macropinocytosis could have potential therapeutic benefits.