Patient-derived orthotopic xenograft models predict chemotherapeutic response in pancreatic ductal adenocarcinoma: an emerging platform for translational research

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer death. Current chemotherapy options are centered on a gemcitabine as backbone. However, the chemotherapy responsive rate and prognosis are still very poor with a five-year survival rate of 13%. Animal models mimicking tumor microenvironment have been used for pre-clinical and therapeutic studies, but the subcutaneous xenograft model does not replicate the clinical location and human PDAC chemotherapy responses. In this study, we used patient-derived orthotopic xenograft (PDOX) mouse models, with tumors localized to the pancreases, that mimic the natural tumor microenvironment, to test the efficacy of chemotherapeutic gemcitabine on PDAC progression and compare to their clinical response. Methods: Totally 71 PDAC patients were consented and their tumor/blood specimens were collected after reviewed by pathologists. Tumor cells from one representative partial/moderate chemo-responding PDAC patients (PaCa23) and one representative poor chemo-responding PDAC patient (PaCa54), were expanded, isolated and intra-pancreas injected to NOD/SCID mice. Gemcitabine (100 mg/kg) was administered weekly by intravenous infusion for 4 weeks. Tumor volumes and mouse body weights were monitored weekly. After mice were euthanized, tumors were collected for tumor weight measurement. Hematoxylin & Eosin staining and OpalTM 4-color immunofluorescence staining were performed for tumor cell profile and tumor microenvironment study. Results: Our PDOX model in both PaCa23 and PaCa54 retains the principal histologic characteristics of their donor tumor with similar infiltration patterns of stromal cells and remains stable across passages. No significant body weight loss was observed in the gemcitabine group. PaCa23 tumor responded to gemcitabine with significantly decreased tumor volume and tumor weight compared to control group (p=0.007 and p=0.01, respectively). PaCa54 tumor poorly responded to gemcitabine without significant tumor weight decrease compared to controls (p>0.05). Conclusion: Our PDOX mouse model successfully recapitulates key histopathological and microenvironmental features of human PDAC and reflects patient-specific responses to gemcitabine treatment. The differential tumor response observed in PaCa23 and PaCa54 models mirrors their respective clinical outcomes, underscoring the predictive value of this platform. This orthotopic model holds significant promise as a preclinical tool for evaluating chemotherapeutic efficacy, guiding personalized therapy strategies, and studying tumor biology within a clinically relevant microenvironment.