Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein
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Abstract
Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate, and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiologic albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC. Cancer Res; 75(3); 544–53. ©2014 AACR.
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Pancreatic cancer cell line KRPC was able to proliferate in the absence of essential amino acids in culture media but obtain amino acids through macropinocytosis from extracellularly degraded albumin protein.
“An earlier study showed that pancreatic cancer cell line KRPC was able to proliferate in the absence of essential amino acids in the culture media but obtain amino acids through macropinocytosis from extracellularly degraded albumin protein [121].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [121]
The Results section reports that KRPC cells proliferated without individual essential amino acids when supplied with albumin, and grew to confluence in amino-acid-free medium supplemented with albumin. Isotope tracing and inhibitor experiments support uptake of extracellular protein by macropinocytosis as a source of amino acids. The paper places protein degradation in lysosomes after uptake, however, not outside the cells as 'extracellularly degraded' suggests. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlbumin is taken up from the interstitium by rapidly proliferating cancer cells and degraded by cell organelles supplying amino acids as building blocks.
“There is evidence that albumin is taken up from the interstitium by rapidly proliferating cancer cells, and is degraded by cell organelles supplying amino acids as building blocks.86”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [86]
The Introduction describes uptake of extracellular proteins by macropinocytosis and their digestion in lysosomes into amino acids. The Results show that albumin supplies amino acids and supports proliferation in cultured pancreatic cancer cells. The paper does not directly show albumin being taken up from the interstitium by rapidly proliferating cancer cells in tumors; it presents that in-tumor nutrient route as a possibility. (LLM, conf=0.84)
Experimental — accuracy not yet measuredProliferation is costly in terms of energy and substrates, and maintaining a persistently raised metabolic rate would be counter-productive if it caused the tumor to become depleted of resources and overloaded with waste.
“However, proliferation is costly in terms of energy and substrates, and maintaining a persistently raised metabolic rate would be counter-productive if it caused the tumor to become depleted of resources and overloaded with waste.3”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [3]
The Introduction says tumor growth has high metabolic demands and that poor perfusion may limit oxygen and nutrients. The Discussion describes PDAC tumors as nutrient-poor, but the paper does not say that a persistently raised metabolic rate would be counterproductive or that tumors become overloaded with waste. Page numbers are not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn 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 [86]
The shift in immune infiltration after Treg depletion follows loss of myCAFs, as Tregs are a significant source of TGF-beta.
“This shift in immune infiltration follows a loss of myCAFs upon Treg depletion, as Tregs proved a significant source of TGF-beta.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [192]
CD4 T cell ablation enabled CD8-mediated regression of PDAC tumors in mice.
“even though CD4 T cell ablation enabled CD8 mediated regression of PDAC tumors in mice”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [192]
Depletion of FoxP3+ Tregs accelerated tumorigenesis due to compensatory myeloid infiltration.
“depletion of FoxP3+ T regulatory cells (Tregs) accelerated tumorigenesis due to compensatory myeloid infiltration192”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [192]
Albumin supplementation restores proliferation of a KRASG12D-driven mouse pancreatic cancer line in medium devoid of all free amino acids.
“Albumin supplementation has even been shown to restore the proliferation of a KRASG12D-driven mouse pancreatic cancer line in the culture medium that was devoid of all free amino acids”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Kamphorst et al., 2015
Cysteine is the second most depleted amino acid in pancreatic tumors compared with normal pancreatic tissue.
“Consistent with its heavy utilization by cancer cells, cysteine was found to be the second most depleted amino acid in pancreatic tumors in comparison to normal pancreatic tissue (Kamphorst et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Kamphorst et al., 2015
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- Authors
- Kamphorst, J. J., Nofal, M., Commisso, C., Hackett, S. R., Lu, W., Grabocka, E., Vander Heiden, M. G., Miller, G., Drebin, J. A., Bar-Sagi, D., Thompson, C. B., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- New York University (US)
- 3Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
- Hospital of the University of Pennsylvania (US)
- 2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Rabinowitz, Joshua D.
- ORCID
- Venue
- Cancer Research
- Published
- 2015-02-01
- Volume
- 75
- Issue
- 3
- Pages
- 544-553
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4316379
- OpenAlex
- W2140814324
- Cited by
- 893
- References
- 36
- Citations by year
- 2026: 59 · 2025: 82 · 2024: 80 · 2023: 101 · 2022: 102 · 2021: 106 · 2020: 80 · 2019: 77 · 2018: 69 · 2017: 60 · 2016: 57 · 2015: 17
- FWCI
- 22.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- PMC
- Funders
- Cancer Research UK (22311)
- National Institutes of Health (UL1TR000038, UL1TR001445)
- National Cancer Institute (R01CA055360, 1R01CA16359-01A1, F31CA186513, P30CA072720, P30CA016087, R01CA163591, P30CA016359)
- National Institute of General Medical Sciences (P50GM071508)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, macropinocytosis, amino acid metabolism, glutamine, essential amino acids, lysosomal degradation, KRAS oncogenic signaling, tumor microenvironment, albumin
- MeSH terms
- Albumins, Amino Acids, Animals, Chromatography, Liquid, Glucose, Glutamine, Humans, Pancreatic Neoplasms, Pinocytosis, Serine, Mass Spectrometry, Stem Cells, Tumor Cells, Cultured, Signal Transduction, Gene Expression Regulation, Neoplastic, Carcinoma, Pancreatic Ductal, Cell Proliferation, Mice
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