Development of an Orthotopic Pancreatic Ductal Adenocarcinoma (PDAC) Patient Derived Xenografts (PDX) Preclinical Model and Characterization of Aquaporin 7 (AQP7) Expression

Abstract

Introduction: Pancreatic cancer is a frequent malignancy associated with poor prognosis. Orthotopic patient-derived xenografts (PDX) represent the cutting edge of translational cancer research in the field of precision medicine. Here, we report the establishment of an orthotopic PDX model of pancreatic ductal adenocarcinoma (PDAC) for the development of novel therapeutic approaches. Method: Tumor samples were collected upon surgery and inoculated into immunocompromised mice. After xenograft development, tumors were compared to patient's original tumor by immunochemistry, cultured and serially transplanted into mice for the determination of tumor growth characteristics. Aquaporin 7 (AQP7) protein expression was studied using Western Blot and immunochemistry. Stem cell characteristics were examined by flow cytometry and limited dilution method. Moreover, activity of selected compounds was studied both in vitro and in vivo. Results: 20 out of 24 engraftments (83.3%) from tissue collected from five patients were successful. Immunohistochemical analysis of representative tumors revealed that they represent the most aggressive and less differentiated population of the patient's tumor. In vitro studies to characterize the expression of AQP7 expression showed that AQP7 is under-expressed in pancreatic cancer. Further in vivo studies to evaluate the activity of AQP7 as single agents or in combination with established drugs are ongoing. Conclusion: These findings uncover the great potential role of PDX for precision medicine and drug discovery, along with the implication of AQP7 in PDAC biology.