Macropinocytosis is a process by which cells internalize extracellular fluid and its contents through large vesicles called macropinosomes. This study shows that oncogenic Ras proteins in transformed cells use macropinocytosis to take in extracellular proteins, which are then broken down into amino acids, including glutamine, that support central carbon metabolism. This process is crucial for the growth of Ras-transformed cells, as their reliance on extracellular glutamine can be reduced by macropinocytic uptake of protein. Inhibition of macropinocytosis in Ras-transformed pancreatic tumor xenografts reduces tumor growth, indicating that this process is a key nutrient supply route for cancer cells. The study demonstrates that oncogenic Ras-expressing cells, such as pancreatic and bladder cancer cells, exhibit increased macropinocytosis compared to wild-type cells. This was confirmed using TMR-dextran uptake assays and fluorescent microscopy. Macropinocytosis was further validated by the dose-dependent inhibition of uptake by EIPA, a known inhibitor of macropinosome formation. Knockdown of K-Ras reduced macropinocytosis, confirming its dependence on oncogenic Ras. The study also shows that oncogenic Ras-expressing cells internalize and degrade extracellular albumin via macropinocytosis, generating amino acids that support cell proliferation. This was demonstrated using DQ-BSA, a fluorescently labeled albumin that only emits light after proteolytic digestion. The degradation of albumin was dependent on lysosomal hydrolases, as evidenced by the prevention of DQ-BSA degradation by bafilomycin A1. The study further shows that the internalization of albumin via macropinocytosis increases intracellular levels of glutamate and α-ketoglutarate, which are essential for central carbon metabolism. This was confirmed by measuring intracellular concentrations of these metabolites in cells grown with or without albumin. Additionally, the study found that protein-derived amino acids enter central carbon metabolism through various pathways, including glutamine anaplerosis, acetyl-CoA metabolism, reductive carboxylation, and serine/glycine cycling. The study also shows that the sensitivity of oncogenic Ras-expressing cells to glutamine deprivation can be reversed by supplementing media with albumin. This was demonstrated using NIH 3T3 cells, which showed increased proliferation when cultured with albumin. The effect was abrogated by EIPA treatment, indicating that macropinocytosis is required for albumin-dependent proliferation. Finally, the study shows that pharmacological inhibition of macropinocytosis in vivo reduces tumor growth in a pancreatic cancer xenograft model. This suggests that targeting macropinocytosis could be a potential therapeutic strategy for cancers that rely on this process for nutrient supply. The findings highlight the importance of macropinMacropinocytosis is a process by which cells internalize extracellular fluid and its contents through large vesicles called macropinosomes. This study shows that oncogenic Ras proteins in transformed cells use macropinocytosis to take in extracellular proteins, which are then broken down into amino acids, including glutamine, that support central carbon metabolism. This process is crucial for the growth of Ras-transformed cells, as their reliance on extracellular glutamine can be reduced by macropinocytic uptake of protein. Inhibition of macropinocytosis in Ras-transformed pancreatic tumor xenografts reduces tumor growth, indicating that this process is a key nutrient supply route for cancer cells. The study demonstrates that oncogenic Ras-expressing cells, such as pancreatic and bladder cancer cells, exhibit increased macropinocytosis compared to wild-type cells. This was confirmed using TMR-dextran uptake assays and fluorescent microscopy. Macropinocytosis was further validated by the dose-dependent inhibition of uptake by EIPA, a known inhibitor of macropinosome formation. Knockdown of K-Ras reduced macropinocytosis, confirming its dependence on oncogenic Ras. The study also shows that oncogenic Ras-expressing cells internalize and degrade extracellular albumin via macropinocytosis, generating amino acids that support cell proliferation. This was demonstrated using DQ-BSA, a fluorescently labeled albumin that only emits light after proteolytic digestion. The degradation of albumin was dependent on lysosomal hydrolases, as evidenced by the prevention of DQ-BSA degradation by bafilomycin A1. The study further shows that the internalization of albumin via macropinocytosis increases intracellular levels of glutamate and α-ketoglutarate, which are essential for central carbon metabolism. This was confirmed by measuring intracellular concentrations of these metabolites in cells grown with or without albumin. Additionally, the study found that protein-derived amino acids enter central carbon metabolism through various pathways, including glutamine anaplerosis, acetyl-CoA metabolism, reductive carboxylation, and serine/glycine cycling. The study also shows that the sensitivity of oncogenic Ras-expressing cells to glutamine deprivation can be reversed by supplementing media with albumin. This was demonstrated using NIH 3T3 cells, which showed increased proliferation when cultured with albumin. The effect was abrogated by EIPA treatment, indicating that macropinocytosis is required for albumin-dependent proliferation. Finally, the study shows that pharmacological inhibition of macropinocytosis in vivo reduces tumor growth in a pancreatic cancer xenograft model. This suggests that targeting macropinocytosis could be a potential therapeutic strategy for cancers that rely on this process for nutrient supply. The findings highlight the importance of macropin