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Updated: May 31, 2026
Immunophenotyping of Orthotopic Homograft (Syngeneic) of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry
Published on: October 9, 2018
Molecular profiling of direct xenograft tumors established from human pancreatic adenocarcinoma after neoadjuvant
Michael P Kim1, Mark J Truty, Woonyoung Choi
1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Background:
Pancreatic adenocarcinoma is among the most resistant of human cancers, yet specific mechanisms of treatment resistance remain poorly understood. Models to study pancreatic cancer resistance remain limited and should reflect in vivo changes that occur within patient tumors. We sought to identify consistent, differentially expressed genes between treatment of naive pancreatic tumors and those exposed to neoadjuvant therapy using a strict, in vivo direct xenograft model system.
Methods:
Over a 42-week period, 12 untreated and treated patient tumors were successfully engrafted into NOD/SCID mice. RNA from each treatment group (5 untreated and 4 treated) was isolated in triplicate and subjected to global gene expression analysis. Consistent gene expression changes with treatment were identified and confirmed using RT-PCR and immunohistochemistry.
Results:
Engraftment of untreated patient tumors was more frequent than treated tumors (17 of 21 versus 16 of 49, P = .0002) but without differences in observed time until tumor formation. The histology of patient tumors was recapitulated in direct xenograft tumors. Relative to untreated tumors, treated tumors consistently demonstrated more than a 2-fold reduction in TGFβ-R2 mRNA expression and more than a 5-fold increase in IGFBP3 expression (P < .0218) and were confirmed by immunohistochemistry.
Conclusion:
Engraftment of human pancreatic tumors into immunodeficient mice prior to and following neoadjuvant therapy is possible and provides an in vivo platform for comparison of global gene expression patterns. The decreased TGFβ-R2 expression and increased IGFBP3 expression among direct xenograft tumors derived from treated tumors relative to untreated tumors suggests a role in therapy resistance and warrants further study.
Insights
Pancreatic cancer resistance mechanisms are unclear. This study used a xenograft model to find gene expression differences between untreated and treated tumors, identifying TGFβ-R2 and IGFBP3 as potential markers of therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pancreatic adenocarcinoma exhibits high treatment resistance, with poorly understood underlying mechanisms.
- Existing models for studying pancreatic cancer resistance are limited and do not fully replicate in vivo tumor changes.
- There is a need for robust in vivo models to investigate gene expression alterations associated with neoadjuvant therapy in pancreatic tumors.
Purpose of the Study:
- To identify consistent, differentially expressed genes between treatment-naive and neoadjuvant therapy-exposed pancreatic tumors.
- To establish and validate a strict, in vivo direct xenograft model system for comparative gene expression analysis.
- To explore potential molecular mechanisms contributing to pancreatic cancer treatment resistance.
Main Methods:
- Engraftment of 12 human pancreatic tumors (untreated and treated) into NOD/SCID mice over 42 weeks.
- Global gene expression analysis of RNA isolated from xenograft tumors (5 untreated, 4 treated).
- Validation of identified gene expression changes using RT-PCR and immunohistochemistry.
Main Results:
- Successful xenograft engraftment of human pancreatic tumors, with histology recapitulating patient tumors.
- Treated tumors showed a >2-fold decrease in TGFβ-R2 mRNA and a >5-fold increase in IGFBP3 mRNA compared to untreated tumors (P < .0218).
- Gene expression changes were confirmed via immunohistochemistry, indicating significant alterations post-neoadjuvant therapy.
Conclusions:
- Direct xenografting of human pancreatic tumors before and after neoadjuvant therapy provides an in vivo platform for gene expression comparison.
- Decreased TGFβ-R2 and increased IGFBP3 expression in treated xenografts suggest a role in pancreatic cancer therapy resistance.
- These findings warrant further investigation into the functional significance of TGFβ-R2 and IGFBP3 in treatment-resistant pancreatic adenocarcinoma.
