Establishment of patient-derived orthotopic xenograft (PDOX) models to represent entire of pancreatic cancer patients

Abstract

Introduction: Patient derived xenograft (PDX) models as the alternative that reflect pathological and molecular features of the original disease have been generated by implanting tumor fragments from primary surgical resection into immune deficient mice subcutaneously. However, PDX studies in pancreatic cancer are scarce since only a small minority of patient-derived sample is resected tissue. Methods: Here, we pioneered the patient derived orthotopic xenograft (PDOX) model from especially non-surgical tumor tissues such as 1) endoscopic ultrasonography-guided/fine-needle aspiration (EUS/FNA) for primary tumor and 2) percutaneous liver biopsy for metastatic tumor as well as surgically resected tissue, with a technique of directly surgical orthotopic implantation into the pancreatic tail. Results: Of 134 patients with pancreatic cancer, only 35 (26%) engrafted and could be propagated beyond passage one. The histopathological characteristics of the PDOX tumors are similar with those of the patient's original tissues. Additionally, genetic alterations were retained between patient tissues (F0) and PDOX tumors (F1∼F3) from the mutation analysis using a comprehensive cancer panel. Moreover, we developed the stable storage method of freezing-thawing-implantation protocol and overcame temporal and economic limit to establish PDOX models. Conclusion: We have demonstrated success in using surgical and nonsurgical specimen to build PDX models that recapitulate tumor complexity and tumor environment,. Because itmight be the valuable drug screening system or development system for targeted therapeutics, we are now using this approach to develop a rich resource of PDOX models for the investigation of therapeutic resistance.