title: Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Jonas
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Keibler
authors.affiliation: Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Han Wei
authors.initials: HW
authors.lastname: Hou
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Alba
authors.initials: A
authors.lastname: Luengo
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jared R
authors.identifier: http://orcid.org/0000-0002-8607-1787
authors.initials: JR
authors.lastname: Mayers
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wyckoff
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Del Rosario
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whitman
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chin
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Condon
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Lammers
authors.affiliation: Bruker Daltronics, Inc., Billerica, Massachusetts, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kellersberger
authors.affiliation: Bruker Daltronics, Inc., Billerica, Massachusetts, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Stall
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
authors.affiliation: New York University School of Medicine, New York University, New York, New York, USA.
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
authors.affiliation: Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jongyoon
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Materials Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cima
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
mesh_terms: D000418:Albumins / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D045744:Cell Line, Tumor; D002849:Chromatography, Gas; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D051379:Mice; D036641:Microscopy, Fluorescence, Multiphoton; D009587:Nitrogen Isotopes; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010873:Pinocytosis; D010956:Plasmapheresis; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis; D012709:Serum Albumin / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000418:Albumins; D000596:Amino Acids; D009587:Nitrogen Isotopes; D011506:Proteins; D012709:Serum Albumin