Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases.

Oncogene
Matthew E BechardOliver G McDonald

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 adequat...Continue Reading

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Citations

Oct 2, 2019·Cancers·Liang YanHaoqiang Ying
May 11, 2019·Clinical & Experimental Metastasis·Demond Williams, Barbara Fingleton
Aug 15, 2020·Nature Communications·Matthew E BechardOliver G McDonald
Nov 27, 2020·Molecular & Cellular Oncology·Oliver G McDonald
Jun 17, 2021·Cellular and Molecular Life Sciences : CMLS·Abudureyimu TuerhongChen Liang
Jan 16, 2022·Oncogene·Rana V SmallingOliver G McDonald

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