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.
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Acknowledgments
This work was supported by the AACR Pancreatic Cancer Action Network Pathway to Leadership grant (OGM), the Vanderbilt GI SPORE (OGM), and the Vanderbilt Digestive Diseases Research Center (OGM).
Author contributions
MEB and OGM performed experiments and cell culture. OGM conceived the work and wrote the manuscript. AEW performed a subset of gene expression analyses. AEW and AVT plotted 3D tumor assay data. JWL and XL performed LC–HRMS, assigned spectra, and edited presentation of the LC–HRMS data. OGM assembled the final figures. All authors agreed to the final version of the manuscript.
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Bechard, M.E., Word, A.E., Tran, A.V. et al. Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases. Oncogene 37, 5248–5256 (2018). https://doi.org/10.1038/s41388-018-0346-5
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DOI: https://doi.org/10.1038/s41388-018-0346-5
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