Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance
Open accessPublished version of a preprint
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analogue gemcitabine is among the most effective therapies to treat PDAC, however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine. Conditioned media from pancreatic stellate cells (PSC), as well as from other fibroblasts, protected PDAC cells from gemcitabine toxicity. The protective effect of PSC-conditioned media was mediated by secretion of deoxycytidine, but not other deoxynucleosides, through equilibrative nucleoside transporters. Deoxycytidine inhibited the processing of gemcitabine in PDAC cells, thus reducing the effect of gemcitabine and other nucleoside analogues on cancer cells. These results suggest that reducing deoxycytidine production in PSCs may increase the efficacy of nucleoside analog therapies. Significance: This study provides important new insight into mechanisms that contribute to gemcitabine resistance in PDAC and suggests new avenues for improving gemcitabine efficacy.
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Deoxycytidine released among these pyrimidines inhibits gemcitabine efficacy, and depletion of myeloid cells in mice sensitizes PDAC tumors to gemcitabine treatment.
“the deoxycytidine released among these pyrimidines inhibits the efficacy of the standard of care chemotherapy gemcitabine, and depletion of myeloid cells in mice sensitizes PDAC tumors to gemcitabine treatment.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [258]
Both TAM- and CAF-released deoxycytidine inhibit gemcitabine efficacy through molecular competition at deoxycytidine kinase.
“both TAM and CAF-released deoxycytidine act to inhibit the efficacy of gemcitabine through molecular competition at deoxycytidine kinase258,259”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [258]
TAMs and other anti-inflammatory macrophages release numerous pyrimidine species that are avidly consumed by PDAC cells.
“TAMs and other anti-inflammatory macrophages release numerous pyrimidine species that are avidly consumed by PDAC cells258.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [258]
Anti-inflammatory macrophages and pancreatic TAMs utilize predominantly mitochondrial bioenergetic programming fueled by fatty acid metabolism.
“anti-inflammatory macrophages and pancreatic TAMs utilize a predominantly mitochondrial bioenergetic metabolic programming, fueled by fatty acid metabolism258.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [258]
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References 48 · Cited by 156
- Authors
- Dalin, S., Sullivan, M. R., Lau, A. N., Grauman-Boss, B., Mueller, H. S., Kreidl, E., Fenoglio, S., Luengo, A., Lees, J. A., Vander Heiden, M. G., Lauffenburger, D. A., & Hemann, M. T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- 1Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
- Massachusetts Institute of Technology (US)
- Corresponding author
- Lauffenburger, Douglas A.
- Hemann, Michael T.
- ORCID
- Venue
- Cancer Research
- Published
- 2019-11-15
- Volume
- 79
- Issue
- 22
- Pages
- 5723-5733
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC7357734
- OpenAlex
- W2971848759
- Cited by
- 156
- References
- 48
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 29 · 2023: 27 · 2022: 29 · 2021: 25 · 2020: 16 · 2019: 1
- FWCI
- 7.42
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Cancer Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | NIH | National Cancer Institute (NCI) (U54-217377, R01-226898, P30-CA14051, K99CA234221)
- MIT Center for Precision Cancer Medicine
- Damon Runyon Cancer Research Foundation (Damon Runyon) (DRG-2241-15)
- David H. Koch Fellowship in Cancer Research
- The Ludwig Center at MIT
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- gemcitabine resistance, pancreatic ductal adenocarcinoma, pancreatic stellate cells, deoxycytidine, tumor stroma, conditioned medium, equilibrative nucleoside transporter, fibroblasts
- MeSH terms
- Gemcitabine, Animals, Antimetabolites, Antineoplastic, Deoxycytidine, Humans, Mice, Inbred C57BL, Pancreatic Neoplasms, Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, HEK293 Cells, Pancreatic Stellate Cells
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