Pancreatic cancer ascites xenograft-an expeditious model mirroring advanced therapeutic resistant disease

Abstract

// Talia Golan 1, 2, * , Chani Stossel 1, * , Michael Schvimer 3 , Dikla Atias 1 , Sharon Halperin 1 , Ella Buzhor 1 , Maria Raitses-Gurevich 1 , Keren Cohen 1 , Sara Pri-Chen 4 , Julie Wilson 5 , Robert E. Denroche 6 , Ilinca Lungu 6 , John M.S. Bartlett 5 , Faridah Mbabaali 5 , Yosef Yarden 7 , Nishanth Belugali Nataraj 7 , Steven Gallinger 5, 6 and Raanan Berger 2, 8 1 Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Pathology Department, Sheba Medical Center, Tel Hashomer, Israel 4 Microsurgery Laboratory, Eye Institute, Sheba Medical Center, Tel Hashomer, Israel 5 Ontario Institute for Cancer Research, Toronto, Canada 6 Department of Surgery, University Health Network, Toronto, Canada 7 Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel 8 Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel * These authors contributed equally to this work Correspondence to: Talia Golan, email: Talia.Golan@sheba.health.gov.il Keywords: pancreatic ductal adenocarcinoma (PDAC), metastatic, ascites, whole genome sequencing (WGS), patient derived xenograft (PDX) Received: September 26, 2016      Accepted: April 04, 2017      Published: April 19, 2017 ABSTRACT Pancreatic ductal adenocarcinoma has limited treatment options. There is an urgent need for developing appropriate pre-clinical models recapitulating metastatic disease, the most common clinical scenario at presentation. Ascites accumulation occurs in up to 20–30% of patients with pancreatic cancer; this milieu represents a highly cellular research resource of metastatic peritoneal spread. In this study, we utilized pancreatic ascites/pleural effusion cancer cells to establish patient derived xenografts. Ascites/pleural effusion-patient derived xenografts were established from twelve independent cases. Xenografts were serially passed in nude mice and tissue bio-specimen banking has been established. Histopathology of emergent tumors demonstrates poorly to moderately differentiated, glandular and mucin producing tumors, mirroring morphology of primary pancreatic cancer tumors. Whole genome sequencing of six patient derived xenografts samples demonstrates common mutations and structural variations similar to those reported in primary pancreatic cancer. Xenograft tumors were dissociated to single-cells and in-vitro drug sensitivity screen assays demonstrated chemo-resistance, correlating with patient clinical scenarios, thus serving as a platform for clinically relevant translational research. Therefore, establishment of this novel ascites/pleural effusion patient derived xenograft model, with extensive histopathology and genomic characterization, opens an opportunity for the study of advanced aggressive pancreatic cancer. Characterization of metastatic disease and mechanisms of resistance to therapeutics may lead to the development of novel drug combinations.