Mammalian tissues rely on a variety of nutrients to support their physiological functions1. 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 understood2,3. Amino acids are essential nutrients for many cancer cells4,5 that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis6,7. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes8 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.
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The authors wish to dedicate this paper to the memory of Katherine Kellersberger. We thank the MIT Department of Chemical Engineering and J. Francois-Hamel for access to bioreactor equipment, R. Bronson for pathological grading of tumors and A. Lau for providing tumor-bearing mice. S.M.D. and A.L. received support from a National Science Foundation Graduate Research Award Fellowship, and support from T32 GM007287 is also acknowledged. O.J. received support from the Koch Institute Frontier Grant and the Prostate Cancer Foundation. J.R.M. acknowledges support from grant F30CA183474 from the NCI and grant T32 GM007753 from NIGMS. M.A.K. and G.S. acknowledge support from NIH grants 1R01 DK075850-01 and 1R01 CA160458-01A1. M.G.V.H. acknowledges support from the Lustgarten Foundation, the Ludwig Center at MIT, the Broad Institute SPARC program, the Burroughs Wellcome Fund, SU2C and the NIH (P30 CA1405141, R01 CA168653). H.W.H. and J.H. acknowledge support by DARPA's Dialysis-Like Therapy (DLT) program under SSC Pacific grant N66001-11-1-4182. This work is also supported by the use of MIT's Microsystems Technology Laboratories.
The authors declare no competing financial interests.
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Davidson, S., Jonas, O., Keibler, M. et al. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat Med 23, 235–241 (2017). https://doi.org/10.1038/nm.4256
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