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Nat Med. 2017 Feb;23(2):235-241. doi: 10.1038/nm.4256. Epub 2016 Dec 26.

Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
3
Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
4
Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
5
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
6
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
7
Bruker Daltronics, Inc., Billerica, Massachusetts, USA.
8
New York University School of Medicine, New York University, New York, New York, USA.
9
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
10
Department of Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
11
Department of Materials Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
12
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

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.

PMID:
28024083
PMCID:
PMC5407288
DOI:
10.1038/nm.4256
[Indexed for MEDLINE]
Free PMC Article

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