Abstract 4937: Comparison of orthotopic and subcutaneous implantation of pancreatic cancer patient-derived xenograft models for drug development

Abstract

Patient derived xenograft (PDX) models of pancreatic cancer provide an excellent platform for understanding human disease, characterizing tumor-initiating cells, and testing of novel therapeutics. Herein, we compared the natural pancreatic microenvironment via orthotopic implantation and the traditional approach of subcutaneous implantation for effects on PDX tumor growth, tumor morphology, cell population diversity, tumorigenic potential, metastatic potential, and response to therapeutics. Two approaches were used: (1) primary human cancer tissue fragments were implanted in orthotopic and subcutaneous environments; and, (2) PDX previously established by subcutaneous engraftment were reimplanted into either an orthotopic or a subcutaneous environment. We report that orthotopically-engrafted primary PDX more closely reflect the gross tumor morphology of the original patient than subcutaneously-derived tumors. In models derived from subcutaneous engraftment, variation of tumor morphology, tumor growth, cell population diversity, and tumorigenic potential between tumors grown in orthotopic and subcutaneous environments were dependent on PDX line; and, stromal infiltration and mucin production were more prominent in the orthotopic background for some PDX models. In addition, we observe increased metastatic potential in orthotopic tumor-bearing mice compared with their subcutaneous counterparts. Tumor metastasis occurred in distal filtering organs, including the lung, liver, lymph nodes, and peritoneal cavity, among others. This result is consistent with the observation of increased circulating tumor cells in the blood of orthotopic tumor bearing mice. Comparison of therapeutic efficacy with gemcitabine chemotherapy and antibody-drug conjugate (ADC) therapy in orthotopic and subcutaneous tumors showed therapeutic response was dependent on PDX line. Interestingly, for PDX lines that exhibited morphological differences between orthotopic and subcutaneous backgrounds, treatment was less effective in the orthotopic microenvironment suggesting the microenvironment alters the ability of therapeutics to impede tumor growth. Reduced therapeutic response was also found to be consistent with reduced ADC uptake and vascularity in orthotopic tumors. Taken together, the orthotopic PDX model serves as a more accurate representation of human pancreatic cancer by displaying stromal-rich morphology, exhibiting metastatic cell behavior, and recapitulating therapeutic response challenges observed in patients. Citation Format: Sarah L. Fong, Marybeth A. Pysz, Kristen D. McKnight, Nicole Taylor, Regina Nieu, Juliet Markeson, Hanna Rammoth, Archana Dilip, Kayla Fasano, Emily Janke, Erica Anderson, Holger Karsunky, Scott Dylla. Comparison of orthotopic and subcutaneous implantation of pancreatic cancer patient-derived xenograft models for drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4937. doi:10.1158/1538-7445.AM2017-4937