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Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Open accessAbstract
Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
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“This especially occurs in nutrient‐deprived states and is regulated by mammalian target of rapamycin complex 1 (mTORC1), controlling protein synthesis.94”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [94]
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In the citing paper
“expression of mutant Ras or c-Src alleles provides cells with a mechanism that allows them to recover free amino acids through the lysosomal degradation of extracellular proteins”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Commisso et al., 2013
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“PDAC cells harboring KRAS∗ rely on increased levels of macropinocytosis for nutrient salvaging to sustain uncontrolled cell growth.14”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [14]
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“a nutrient salvage process that supports oncogenic growth.14”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [14]
In the citing paper
“PDAC cells utilize macropinocytosis to obtain amino acids through the uptake and degradation of albumin and collagen230–232”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [230]
In the citing paper
“PDAC cells can utilize macropinocytosis to obtain proline from CAF produced collagen230.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [230]
In the citing paper
“Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling.”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Commisso et al., 2013
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“Recent studies have shown that macropinocytosis of circulating proteins (especially albumin) could supply amino acids to nutrient-deprived cancer cells (Commisso et al., 2013).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Commisso et al., 2013
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“These results suggested that exosomes themselves might be acting as source of metabolites in a manner similar to macropinocytosis observed recently in Kras expressing pancreatic cancer cells (Commisso et al., 2013).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Commisso et al., 2013
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Metadata
- Authors
- Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., Rabinowitz, J. D., Metallo, C. M., Vander Heiden, M. G., & Bar-Sagi, D.
- Affiliations
- New York University (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- University of California San Diego (US)
- Princeton University (US)
- Hospital of the University of Pennsylvania (US)
- Memorial Sloan Kettering Cancer Center (US)
- ORCID
- Venue
- Nature
- Published
- 2013-05-12
- Volume
- 497
- Issue
- 7451
- Pages
- 633-637
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3810415
- OpenAlex
- W2129917557
- Cited by
- 1,683
- References
- 31
- Citations by year
- 2026: 120 · 2025: 130 · 2024: 130 · 2023: 136 · 2022: 162 · 2021: 186 · 2020: 166 · 2019: 135 · 2018: 129 · 2017: 113 · 2016: 119 · 2015: 79 · 2014: 56 · 2013: 20
- FWCI
- 52.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- National Cancer Institute (R01CA055360, P01CA104838, R01CA105463, P30CA014051, P01CA117969, P30CA016087, R01CA163591)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- macropinocytosis, oncogenic Ras, amino acid supply, glutamine addiction, cancer metabolism, macropinosomes, protein degradation, pancreatic tumours, nutrient uptake, cancer therapy
- MeSH terms
- Amino Acids, Animals, Biological Transport, Carbon, Cell Line, Transformed, Cell Transformation, Neoplastic, Disease Models, Animal, Female, Glutamine, Mice, Nude, Pancreatic Neoplasms, Pinocytosis, Oncogene Protein p21(ras), NIH 3T3 Cells, Cell Line, Tumor, Cell Proliferation, Mice, Proteolysis
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