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Updated: Dec 12, 2025
An Orthotopic Resectional Mouse Model of Pancreatic Cancer
Published on: September 24, 2020
Pancreatic cancer resistance conferred by stellate cells: looking for new preclinical models
Pei Pei Che1,2, Alessandro Gregori2, Omidreza Firuzi3
1Department of Radiation Oncology, Amsterdam University Medical Centers, Location VUMC, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor response to chemo- and (modest-dose conventionally fractionated) radio-therapy. Emerging evidence suggests that pancreatic stellate cells (PSCs) secrete deoxycytidine, which confers resistance to gemcitabine. In particular, deoxycytidine was detected by analysis of metabolites in fractionated media from different mouse PSCs, showing that it caused PDAC cells chemoresistance by reducing the capacity of deoxycytidine kinase (dCK) for gemcitabine phosphorylation. However, data on human models are missing and dCK expression was not associated with clinical efficacy of gemcitabine. We recently established co-culture models of hetero-spheroids including primary human PSCs and PDAC cells showing their importance as a platform to test the effects of cancer- and stroma-targeted drugs. Here, we discuss the limitations of previous studies and the potential use of above-mentioned models to study molecular mechanisms underlying chemo- and radio-resistance.
Insights
Pancreatic stellate cells secrete deoxycytidine, causing gemcitabine resistance in pancreatic cancer. Human co-culture models are crucial for studying this chemoresistance mechanism and developing new therapies.
Area of Science:
- Oncology
- Cancer Biology
- Drug Resistance
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits poor response to chemotherapy and radiotherapy.
- Pancreatic stellate cells (PSCs) are implicated in conferring chemoresistance to gemcitabine via deoxycytidine secretion.
- Previous studies in mouse models suggest deoxycytidine reduces gemcitabine phosphorylation by deoxycytidine kinase (dCK), but human data is lacking.
Purpose of the Study:
- To address the lack of human data regarding PSC-mediated chemoresistance in PDAC.
- To highlight the limitations of previous studies and the need for human models.
- To discuss the potential of human PSC-PDAC co-culture hetero-spheroid models for studying resistance mechanisms.
Main Methods:
- Analysis of metabolites in conditioned media from mouse PSCs.
- Establishment of co-culture hetero-spheroid models using primary human PSCs and PDAC cells.
- Discussion of limitations in existing research and proposed future directions.
Main Results:
- Deoxycytidine secreted by PSCs was identified as a mediator of gemcitabine chemoresistance in PDAC cells.
- Deoxycytidine was shown to reduce the phosphorylation capacity of deoxycytidine kinase (dCK) for gemcitabine in mouse models.
- dCK expression levels did not correlate with the clinical efficacy of gemcitabine in previous studies.
Conclusions:
- Human PSC-PDAC co-culture models offer a valuable platform for investigating chemoresistance mechanisms.
- Understanding the role of deoxycytidine and PSCs is critical for developing effective pancreatic cancer therapies.
- Further research using human models is needed to overcome gemcitabine resistance in PDAC.
