Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases.

Published

Journal Article

Pancreatic ductal adenocarcinoma (PDAC) adopts several unique metabolic strategies to support primary tumor growth. Whether additional metabolic strategies are adopted to support metastatic tumorigenesis is less clear. This could be particularly relevant for distant metastasis, which often follows a rapidly progressive clinical course. Here we report that PDAC distant metastases evolve a unique series of metabolic reactions to maintain activation of the anabolic glucose enzyme phosphogluconate dehydrogenase (PGD). PGD catalytic activity was recurrently elevated across distant metastases, and modulating PGD activity levels dictated tumorigenic capacity. Metabolomics data raised the possibility that distant metastases evolved a core pentose conversion pathway (PCP) that converted glucose-derived metabolites into PGD substrate, thereby hyperactivating the enzyme. Consistent with this, each individual metabolite in the PCP stimulated PGD catalysis in distant metastases, and knockdown of each individual PCP enzyme selectively impaired tumorigenesis. We propose that the PCP manufactures PGD substrate outside of the rate-limiting oxidative pentose phosphate pathway (oxPPP). This enables PGD-dependent tumorigenesis by providing adequate substrate to fuel high catalytic activity, and raises the possibility that PDAC distant metastases adopt their own unique metabolic strategies to support tumor growth.

Full Text

Duke Authors

Cited Authors

  • Bechard, ME; Word, AE; Tran, AV; Liu, X; Locasale, JW; McDonald, OG

Published Date

  • September 2018

Published In

Volume / Issue

  • 37 / 38

Start / End Page

  • 5248 - 5256

PubMed ID

  • 29849117

Pubmed Central ID

  • 29849117

Electronic International Standard Serial Number (EISSN)

  • 1476-5594

International Standard Serial Number (ISSN)

  • 0950-9232

Digital Object Identifier (DOI)

  • 10.1038/s41388-018-0346-5

Language

  • eng