Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases

Matthew E. Bechard, Anna E. Word, Amanda V. Tran, Xiaojing Liu, Jason W. Locasale, Oliver G. McDonald

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5248-5256
Number of pages9
JournalOncogene
Volume37
Issue number38
DOIs
StatePublished - Sep 20 2018
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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