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Updated: May 16, 2026
An Orthotopic Resectional Mouse Model of Pancreatic Cancer
Published on: September 24, 2020
Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma
Reena Shakya1, Tamas Gonda, Michael Quante
1Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2'-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5-mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAF), along with increased amounts of 5-hydroxymethyl-cytosine (5-HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early-treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the CAFs. Expression profiling and immunohistochemistry highlighted DAC induction of STAT1 in the tumors, and DAC plus IFN-γ produced an additive antiproliferative effect on PDAC cells. DAC induced strong expression of the testis antigen deleted in azoospermia-like (DAZL) in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
Insights
Epigenetic therapy using 5-aza-2'-deoxycytidine (DAC) showed promise against pancreatic ductal adenocarcinoma (PDAC). DAC slowed tumor progression and extended survival in mice by targeting both cancer cells and their supportive stroma.
Area of Science:
- Oncology
- Epigenetics
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options.
- Epigenetic alterations, including DNA methylation changes, are implicated in PDAC development and progression.
- Cancer-associated myofibroblasts (CAFs) within the tumor stroma contribute to PDAC aggressiveness.
Purpose of the Study:
- To evaluate the efficacy of the DNA demethylating agent 5-aza-2 -deoxycytidine (DAC) in an aggressive mouse model of PDAC.
- To investigate the effects of DAC on DNA methylation patterns and tumor progression in both epithelial and stromal compartments.
- To explore potential mechanisms of DAC action, including its impact on CAFs and immune-related pathways.
Main Methods:
- Utilized an aggressive mouse model of stromal-rich PDAC (KPC-Brca1 mice).
- Administered DAC to assess its impact on tumor progression, survival, and DNA methylation (5-methyl-cytosine and 5-hydroxymethyl-cytosine).
- Employed mixing-allografting, proliferation indices, expression profiling, and immunohistochemistry to analyze treatment efficacy and mechanisms.
Main Results:
- DAC treatment reduced DNA methylation, slowed PDAC progression, and significantly extended survival in an early-treatment protocol.
- Later initiation of DAC showed transient tumor growth inhibition without adverse effects.
- Escaping tumors exhibited sarcomatoid transformation and CAF disappearance, indicating DAC's effect on both malignant cells and CAFs.
- DAC induced STAT1 expression and, in combination with IFN-γ, showed additive antiproliferative effects on PDAC cells.
- DAC treatment upregulated deleted in azoospermia-like (DAZL) expression in CAFs.
Conclusions:
- DAC demonstrates significant in vivo efficacy against PDAC by targeting both malignant epithelial cells and cancer-associated myofibroblasts.
- The study provides a strong rationale for combining hypomethylating agents like DAC with cytokines and immunotherapy for PDAC treatment.
- DAC's ability to modulate the tumor microenvironment and induce specific gene expression warrants further clinical investigation.
