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Cancer Res. 2015 Feb 1;75(3):544-53. doi: 10.1158/0008-5472.CAN-14-2211.

Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.

Author information

1
Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, New Jersey.
2
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
3
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Boston, Massachusetts.
4
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.
5
Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
6
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
7
Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, New Jersey. joshr@princeton.edu.

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.

PMID:
25644265
PMCID:
PMC4316379
DOI:
10.1158/0008-5472.CAN-14-2211
[Indexed for MEDLINE]
Free PMC Article

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