The study investigates the role of macropinocytosis in Ras-transformed cells, focusing on the internalization and degradation of extracellular proteins to supply amino acids. Macropinocytosis is a process where large, heterogeneous vesicles called macropinosomes internalize extracellular fluid and its contents. The authors show that oncogenic Ras proteins stimulate macropinocytosis, which is crucial for the transformed phenotype. Specifically, they find that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell, where it undergoes proteolytic degradation, producing amino acids including glutamine. This degradation can be inhibited by the macropinocytic uptake of protein, and the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by this mechanism. Pharmacological inhibition of macropinocytosis compromises the growth of Ras-transformed pancreatic tumor xenografts, suggesting its importance in tumor nutrient uptake. The study also demonstrates that macropinocytosis-mediated internalization and degradation of albumin can sustain tumor cell proliferation by providing glutamine and other amino acids. These findings highlight macropinocytosis as a critical mechanism for cancer cells to support their unique metabolic needs and suggest potential therapeutic targets in certain cancers.The study investigates the role of macropinocytosis in Ras-transformed cells, focusing on the internalization and degradation of extracellular proteins to supply amino acids. Macropinocytosis is a process where large, heterogeneous vesicles called macropinosomes internalize extracellular fluid and its contents. The authors show that oncogenic Ras proteins stimulate macropinocytosis, which is crucial for the transformed phenotype. Specifically, they find that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell, where it undergoes proteolytic degradation, producing amino acids including glutamine. This degradation can be inhibited by the macropinocytic uptake of protein, and the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by this mechanism. Pharmacological inhibition of macropinocytosis compromises the growth of Ras-transformed pancreatic tumor xenografts, suggesting its importance in tumor nutrient uptake. The study also demonstrates that macropinocytosis-mediated internalization and degradation of albumin can sustain tumor cell proliferation by providing glutamine and other amino acids. These findings highlight macropinocytosis as a critical mechanism for cancer cells to support their unique metabolic needs and suggest potential therapeutic targets in certain cancers.