Bhuwan Giri1, Anthony Ferrantella1, Prateek Sharma1, Tejeshwar Jain1, Harrys K C Jacob1, Shrey Modi1, Saba Kurtom2, Pooja Roy1, Vrishketan Sethi1, Sulagna Banerjee1, Nipun Merchant3, Sundaram Ramakrishnan1, Ashok Saluja1, Vikas Dudeja4. 1. DeWitt Duaghtry Family Department of Surgery, University of Miami, Miami, FL, USA. 2. Department of Surgery, Virginia Common Wealth University, Richmond, VA, USA. 3. Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, 1501 NW 10th Ave, Miami, FL, 33136, USA. 4. Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, 1501 NW 10th Ave, Miami, FL, 33136, USA. vikas.dudeja@med.miami.edu.
Abstract
BACKGROUND: Even after surgical resection, most patients with localized pancreatic ductal adenocarcinoma (PDAC) succumb to disease recurrence. Current animal models do not recapitulate this pattern of disease recurrence. Our goal was to develop a clinically relevant, immunocompetent model of PDAC resection to study recurrence and evaluate therapy. METHODS: Pancreatic cancer cells derived from tumors arising in KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice were co-injected with stromal cells (pancreatic stellate cells) into the pancreas of immunocompetent mice to simulate the stroma-rich tumors seen in human PDAC. After allowing tumors to form, we resected these localized tumors and followed the mice for tumor recurrence. Circulating tumor cells (CTCs) were isolated, and systemic chemotherapy or immunotherapy was administered following tumor resection. RESULTS: Tumors formed by co-injection of KPC cells and stromal cells demonstrated a dense desmoplastic reaction similar to that seen in human disease. Resection at days 15 and 21 after implantation revealed uniform tumor volumes of 92 ± 19 mm3 on day 15 and 444 ± 54 mm3 on day 21. Histology of resected tumors showed negative margins. Resembling human PDAC, mice that underwent resection showed improved median survival (58 vs 47 days) but most animals developed intra-abdominal recurrence on follow-up. Adjuvant chemotherapy (median survival 69 vs 58 days), but not immunotherapy (median survival 69 vs 65 days) tended towards improved survival as seen in human disease. Circulating tumor cells were reliably identified from mice with and without resection, suggesting utility of this model in studying tumor metastases and recurrence. CONCLUSION: We describe an immunocompetent animal model that recapitulates human disease in morphology and recurrence patterns. We show that it can be used to evaluate therapy in clinical scenarios associated with surgical resection and may help characterize factors responsible for disease recurrence.
BACKGROUND: Even after surgical resection, most patients with localized pancreatic ductal adenocarcinoma (PDAC) succumb to disease recurrence. Current animal models do not recapitulate this pattern of disease recurrence. Our goal was to develop a clinically relevant, immunocompetent model of PDAC resection to study recurrence and evaluate therapy. METHODS: Pancreatic cancer cells derived from tumors arising in KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice were co-injected with stromal cells (pancreatic stellate cells) into the pancreas of immunocompetent mice to simulate the stroma-rich tumors seen in human PDAC. After allowing tumors to form, we resected these localized tumors and followed the mice for tumor recurrence. Circulating tumor cells (CTCs) were isolated, and systemic chemotherapy or immunotherapy was administered following tumor resection. RESULTS: Tumors formed by co-injection of KPC cells and stromal cells demonstrated a dense desmoplastic reaction similar to that seen in human disease. Resection at days 15 and 21 after implantation revealed uniform tumor volumes of 92 ± 19 mm3 on day 15 and 444 ± 54 mm3 on day 21. Histology of resected tumors showed negative margins. Resembling human PDAC, mice that underwent resection showed improved median survival (58 vs 47 days) but most animals developed intra-abdominal recurrence on follow-up. Adjuvant chemotherapy (median survival 69 vs 58 days), but not immunotherapy (median survival 69 vs 65 days) tended towards improved survival as seen in human disease. Circulating tumor cells were reliably identified from mice with and without resection, suggesting utility of this model in studying tumor metastases and recurrence. CONCLUSION: We describe an immunocompetent animal model that recapitulates human disease in morphology and recurrence patterns. We show that it can be used to evaluate therapy in clinical scenarios associated with surgical resection and may help characterize factors responsible for disease recurrence.
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