Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors
Open accessAbstract
Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo.
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In rapidly proliferating cells in cancer, serum albumin can be transported into cells and cell organelles, where it can be degraded to its component amino acids acting as building blocks.
“However, there is evidence in rapidly proliferating cells in cancer that serum albumin can be transported into cells and cell organelles, where it can be degraded to its component amino acids acting as building blocks.84, 85, 86, 87, 88”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [84]
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- Authors
- Davidson, S. M., Jonas, O., Keibler, M. A., Hou, H. W., Luengo, A., Mayers, J. R., Wyckoff, J., Del Rosario, A. M., Whitman, M., Chin, C. R., Condon, K. J., Lammers, A., Kellersberger, K. A., Stall, B. K., Stephanopoulos, G., Bar-Sagi, D., Han, J., Rabinowitz, J. D., Cima, M. J., Langer, R., & Vander Heiden, M. G.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Massachusetts Institute of Technology (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Bruker (United States) (US)
- Princeton University (US)
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-12-26
- Volume
- 23
- Issue
- 2
- Pages
- 235-241
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5407288
- OpenAlex
- W2564262333
- Cited by
- 331
- References
- 42
- Citations by year
- 2026: 12 · 2025: 29 · 2024: 30 · 2023: 21 · 2022: 51 · 2021: 45 · 2020: 47 · 2019: 29 · 2018: 40 · 2017: 26
- FWCI
- 13.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- National Cancer Institute (R21CA177391, R01CA168653, F30CA183474, DP1CA174420, R01CA160458, P30CA014051)
- National Institute of General Medical Sciences (T32GM007753, T32GM007287)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075850)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- pancreatic cancer, macropinocytosis, albumin, amino acid metabolism, tumor microenvironment, nutrient acquisition, plasma exchange, implantable microdevices
- MeSH terms
- Albumins, Amino Acids, Animals, Chromatography, Gas, Disease Models, Animal, Extracellular Space, Nitrogen Isotopes, Pancreatic Neoplasms, Pinocytosis, Plasmapheresis, Proteins, Serum Albumin, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Carcinoma, Pancreatic Ductal, Microscopy, Fluorescence, Multiphoton, Cell Line, Tumor, Mice, Proteolysis
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