title: Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.
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.
authors: Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, New Jersey.
authors: Jurre J
authors: JJ
authors: Kamphorst
authors: Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, New Jersey.
authors: Michel
authors: M
authors: Nofal
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Cosimo
authors: C
authors: Commisso
authors: Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, New Jersey.
authors: Sean R
authors: SR
authors: Hackett
authors: Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, New Jersey.
authors: Wenyun
authors: W
authors: Lu
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Elda
authors: E
authors: Grabocka
authors: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Matthew G
authors: MG
authors: Vander Heiden
authors: Department of Surgery, New York University School of Medicine, New York, New York. Department of Cell Biology, New York University School of Medicine, New York, New York.
authors: George
authors: G
authors: Miller
authors: Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Jeffrey A
authors: JA
authors: Drebin
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Dafna
authors: D
authors: Bar-Sagi
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Craig B
authors: CB
authors: Thompson
authors: Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, New Jersey. joshr@princeton.edu.
authors: Joshua D
authors: JD
authors: Rabinowitz
mesh_terms: D000418:Albumins / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010873:Pinocytosis; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014407:Tumor Cells, Cultured
chemical_list: D000418:Albumins; D000596:Amino Acids; D005973:Glutamine; D012694:Serine; D005947:Glucose
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