Abstract
PDACs gain necessary amino acids via macropinocytosis and degradation of extracellular proteins.
Major finding: PDACs gain necessary amino acids via macropinocytosis and degradation of extracellular proteins.
Approach: Miniaturized plasma exchange with labeled albumin allows direct observation of protein catabolism in vivo.
Impact: Increased albumin uptake by PDACs may allow for improved therapeutic delivery via albumin conjugation.
Amino acids are required for the growth of many cancer cells and may be obtained via the scavenging and catabolism of extracellular protein through macropinocytosis. Although many pancreatic cancers have elevated levels of some amino acids, it has not been directly shown that extracellular proteins are catabolized in vivo. As albumin is the most abundant extracellular protein in blood and tissue and serum albumin is reduced in patients with cancer, Davidson, Jonas and colleagues used labeled albumin in a miniaturized plasma exchange assay to determine if albumin is used as a tumor nutrient source in vivo. Compared to control mice, mice bearing pancreatic ductal adenocarcinomas (PDAC) exhibited increased levels of labeled albumin-derived amino acids in the blood, indicative of albumin degradation. Further, the concentration of labeled albumin peptides and labeled amino acids was higher in PDAC tissue compared to normal pancreas, suggesting that tumors exhibited increased albumin uptake and breakdown compared to normal pancreas. Using an implantable device to deliver fluorescently labeled albumin to the tumor microenvironment of PDAC tumors revealed that PDAC cells internalized albumin via macropinocytosis. Albumin degradation was detected in pancreatic cancer cells, but not detected in nontumor regions of the pancreas. In addition, labeled fibronectin was also internalized by PDAC cells, but not normal pancreas cells, suggesting that pancreatic tumors can consume other extracellular proteins in their environment. The lysosome was involved in catabolism, as degradation of albumin could be reduced by the lysosomal inhibitor hydroxychloroquine. Moreover, inhibiting macropinocytosis resulted in local tumor amino acid depletion, further confirming that a large portion of tumor amino acids are derived from macropinocytosis and catabolism of extracellular proteins. The development of methods to directly observe albumin catabolism provides direct evidence of extracellular protein degradation by pancreatic tumors and suggests a mechanism by which albumin conjugation may improve therapeutic agent delivery.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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