Pancreatic cancer ascites xenograft–an expeditious model mirroring advanced therapeutic resistant disease
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Talia Golan1,2,*, Chani Stossel1,*, Michael Schvimer3, Dikla Atias1, Sharon Halperin1, Ella Buzhor1, Maria Raitses-Gurevich1, Keren Cohen1, Sara Pri-Chen4, Julie Wilson5, Robert E. Denroche6, Ilinca Lungu6, John M.S. Bartlett5, Faridah Mbabaali5, Yosef Yarden7, Nishanth Belugali Nataraj7, Steven Gallinger5,6 and Raanan Berger2,8
1Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel
2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
3Pathology Department, Sheba Medical Center, Tel Hashomer, Israel
4Microsurgery Laboratory, Eye Institute, Sheba Medical Center, Tel Hashomer, Israel
5Ontario Institute for Cancer Research, Toronto, Canada
6Department of Surgery, University Health Network, Toronto, Canada
7Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
8Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel
*These authors contributed equally to this work
Talia Golan, email: [email protected]
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
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.
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