Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of improved preclinical models to test novel anticancer strategies. Here, we developed four orthotopic mouse models using primary human PDAC cells genetically engineered to express firefly- and Gaussia luciferase, simplifying the ability to monitor tumor growth and metastasis longitudinally in individual animals with MRI and high-frequency ultrasound. In these models, we conducted detailed histopathologic and immunohistochemical analyses on paraffin-embedded pancreatic tissues and metastatic lesions in liver, lungs, and lymph nodes. Genetic characteristics were compared with the originator tumor and primary tumor cells using array-based comparative genomic hybridization, using frozen specimens obtained by laser microdissection. Notably, the orthotopic human xenografts in these models recapitulated the phenotype of human PDACs, including hypovascular and hypoxic areas. Pursuing genomic and immunohistochemical evidence revealed an increased copy number and overexpression of c-Met in one of the models; we examined the preclinical efficacy of c-Met inhibitors in vitro and in vivo. In particular, we found that crizotinib decreased tumor dimension, prolonged survival, and increased blood and tissue concentrations of gemcitabine, synergizing with a cytidine deaminase-mediated mechanism of action. Together, these more readily imaged orthotopic PDAC models displayed genetic, histopathologic, and metastatic features similar to their human tumors of origin. Moreover, their use pointed to c-Met as a candidate therapeutic target in PDAC and highlighted crizotinib and gemcitabine as a synergistic combination of drugs warranting clinical evaluation for PDAC treatment.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths [1, 2]
Analysis of cytidine deaminase (CDA) and reactive oxygen species activity Because CDA is the main enzyme in gemcitabine catabolism, we evaluated its enzymatic activity in cells, as well as blood samples and tumor tissues from PDAC-3-FM-GC mice, as described in the Supplementary Methods
Because several studies in patients with PDAC and genetically engineered mouse models (GEMM) PDAC suggest that poor drug delivery and response is attributable to highly desmoplastic and hypovascular tumors [10, 28], it is important that our models recapitulate these environmental factors
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths [1, 2]. The prognosis of this malignancy has not improved in the past decade, with less than 5% of patients alive 5 years after diagnosis [3]. This dismal outcome may be Authors' Affiliations: Departments of 1Medical Oncology, 2Hematology, 3Neurosurgery and Pediatric Oncology/Hematology, Neuro-oncology Research Group, VU University Medical Center; 4Diagnostic Oncology Division, Netherlands Cancer Institute; 5VisualSonics, Amsterdam, the Netherlands; 6Departments of Neurology and Pediatrics, Stanford University School of Medicine, Stanford, California; 7Division of Surgical Pathology, 8Division of General and Transplant Surgery, University of Pisa, Pisa, Italy; and 9Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
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