Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions

Nat Commun. 2017 Jul 7:8:16031. doi: 10.1038/ncomms16031.

Abstract

Tissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited. We show PDAC cells are able to take up collagen fragments, which can promote PDAC cell survival under nutrient limited conditions, and that collagen-derived proline contributes to PDAC cell metabolism. Finally, we show that proline oxidase (PRODH1) is required for PDAC cell proliferation in vitro and in vivo. Collectively, our results indicate that PDAC extracellular matrix represents a nutrient reservoir for tumour cells highlighting the metabolic flexibility of this cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Collagen / chemistry
  • Collagen / metabolism*
  • Extracellular Matrix / chemistry
  • Extracellular Matrix / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Proline / metabolism*
  • Proline Oxidase / genetics*
  • Proline Oxidase / metabolism
  • Signal Transduction

Substances

  • Collagen
  • Proline
  • P4HA3 protein, human
  • Procollagen-Proline Dioxygenase
  • Proline Oxidase
  • PRODH protein, human
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • MMP9 protein, human
  • Matrix Metalloproteinase 9