Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens

• Published in: PloS one Vol. 8; no. 10; p. e77065
• Main Authors: Walters, Dustin M, Stokes, Jayme B, Adair, Sara J, Stelow, Edward B, Borgman, Cheryl A, Lowrey, Bryce T, Xin, Wenjun, Blais, Edik M, Lee, Jae K, Papin, Jason A, Parsons, J Thomas, Bauer, Todd W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.10.2013; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animal models; Animals; B cells; Bioinformatics; Biology; Biomarkers; Biomedical engineering; Cancer metastasis; Cancer therapies; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell culture; Cell Line, Tumor; Chemotherapy; Clinical trials; Cluster Analysis; Correlation coefficient; Correlation coefficients; Cytokines - metabolism; Epidermal growth factor receptors; ErbB Receptors - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene mutation; Genes; Health aspects; Health sciences; Humans; Immunology; K-Ras protein; Kaplan-Meier Estimate; Kinases; Laboratory animals; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Lung cancer; Medical research; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pathology; Patients; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - secondary; Peritoneum; Protein-tyrosine kinase receptors; Public health; ras Proteins - genetics; Smad4 protein; Smad4 Protein - genetics; Surgery; Survival; Transplantation, Heterologous; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumors; Tyrosine; Xenografts; United States > US; Virginia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0077065

Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC. Human PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase activation, and cytokine expression. Fifteen human PDACs were propagated orthotopically in mice. Xenograft-bearing mice developed peritoneal and liver metastases. Time to tumor growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, P53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines. The orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy.