Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases
Open accessAbstract
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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Comparison of primary and metastatic PDAC patient tumors revealed upregulation of anabolic glucose metabolism and a concurrent dependence on the oxidative pentose phosphate pathway during metastasis evolution.
“Comparison of the epigenetic and metabolic state of primary vs. metastatic PDAC patient tumors revealed the upregulation of anabolic glucose metabolism with a concurrent dependence on the oxidative pentose phosphate pathway during the evolution of metastasis241.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [241]
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Sharma, N., Bhushan, A., He, J., Kaushal, G., & Bhardwaj, V. (2020) · Figshare · doi:10.6084/m9.figshare.12986349
Sharma, N., Bhushan, A., He, J., Kaushal, G., & Bhardwaj, V. (2020) · Figshare · doi:10.6084/m9.figshare.12986355
Sharma, N., Bhushan, A., He, J., Kaushal, G., & Bhardwaj, V. (2020) · Figshare · doi:10.6084/m9.figshare.12986343
Sharma, N., Bhushan, A., He, J., Kaushal, G., & Bhardwaj, V. (2020) · Figshare · doi:10.6084/m9.figshare.12986346
Sharma, N., Bhushan, A., He, J., Kaushal, G., & Bhardwaj, V. (2020) · Figshare · doi:10.6084/m9.figshare.12986340
- Authors
- Bechard, M. E., Word, A. E., Tran, A. V., Liu, X., Locasale, J. W., & McDonald, O. G.
- Affiliations
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Duke University (US)
- Vanderbilt-Ingram Cancer Center (US)
- Corresponding author
- McDonald, Oliver G.
- Venue
- Oncogene
- Published
- 2018-05-30
- Volume
- 37
- Issue
- 38
- Pages
- 5248-5256
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC6692915
- OpenAlex
- W2806061720
- Cited by
- 35
- References
- 55
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 15 · 2019: 2 · 2018: 1
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od021630-01, 1s10od018164-01)
- National Cancer Institute (P50CA095103, R01CA222594)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- pancreatic ductal adenocarcinoma, distant metastasis, phosphogluconate dehydrogenase, cancer metabolism, carcinogenesis, oxidative pentose phosphate pathway, glucose metabolism
- MeSH terms
- Humans, Neoplasm Metastasis, Pancreatic Neoplasms, Pentose Phosphate Pathway, Cell Line, Tumor, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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