Successful application of endoscopic ultrasound-guided fine needle biopsy to establish pancreatic patient-derived tumor xenografts: a pilot study

Els Hermans; Schalk W. Van der Merwe; Jeroen Depreeuw; Jeroen Dekervel; Enrico Radaelli; Tania Roskams; Jos van Pelt Jos; Baki Topal; Chris Verslype; Hans Prenen; Werner Van Steenbergen; Frederik Nevens; Diether Lambrechts; Frédéric Amant

doi:10.1055/s-0042-113597

Endoscopy, Inhaltsverzeichnis

Endoscopy 2016; 48(11): 1016-1022
DOI: 10.1055/s-0042-113597

Innovations and brief communication

Successful application of endoscopic ultrasound-guided fine needle biopsy to establish pancreatic patient-derived tumor xenografts: a pilot study

Els Hermans^*

¹Laboratory of Gynecologic Oncology, Department of Oncology, University of Leuven, Leuven, Belgium

,

Schalk W. Van der Merwe^*

²Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium

³Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium

,

Jeroen Depreeuw

¹Laboratory of Gynecologic Oncology, Department of Oncology, University of Leuven, Leuven, Belgium

⁴Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium

⁵VIB, Vesalius Research Center, Leuven, Belgium

,

Jeroen Dekervel

²Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium

³Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium

,

Enrico Radaelli

⁶Center for the Biology of Disease, KU Leuven Center for Human Genetics – InfraMouse, VIB, University of Leuven, Leuven, Belgium

,

Tania Roskams

⁷Division of Translational Cell & Tissue Research, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium

,

Jos van Pelt Jos

²Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium

,

Baki Topal

⁸Department of Abdominal Surgery, University of Leuven, Leuven, Belgium

,

Chris Verslype

²Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium

³Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium

,

Hans Prenen

²Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium

,

Werner Van Steenbergen

²Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium

,

Frederik Nevens

²Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium

,

Diether Lambrechts

⁴Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium

⁵VIB, Vesalius Research Center, Leuven, Belgium

,

Frédéric Amant

¹Laboratory of Gynecologic Oncology, Department of Oncology, University of Leuven, Leuven, Belgium

⁹Antoni van Leeuwenhoek, Nederlands Kanker Instituut, Centrum Gynecologische Oncologie Amsterdam (CGOA), Amsterdam, The Netherlands

› Institutsangaben

Abstract

Background and study aim: Typically, pancreatic patient-derived tumor xenografts (PDXs) are established by transplanting large tumor biopsies obtained through invasive surgery approaches into immunocompromised mice. We aimed to develop pancreatic PDXs by transplanting tumor tissue acquired by endoscopic ultrasound (EUS)-guided fine needle biopsies (FNB), assess take rates compared to surgery-derived PDXs, and demonstrate the histological and genetic resemblance to the original tumor.

Patients and methods: Biopsies of untreated pancreatic carcinoma were collected at surgery and during EUS and processed to generate PDXs.

Results: By centrifugation of FNB-derived tissue prior to engraftment, we achieved an engraftment rate of 60 % (6/10). Despite a decrease in stromal tissue, the general morphology of FNB-derived PDXs was conserved as assessed by histopathology. At the genetic level, somatic mutation and copy number profiles were largely similar to the primary tumor.

Conclusion: We show that it is technically feasible to establish pancreatic PDXs using a minimally invasive sampling technique, such as EUS-FNB. Although only a limited amount of tumor tissue was acquired, we obtained results similar to those from surgery-derived PDXs.

Volltext

Referenzen

References
1 Vincent A, Herman J, Schulick R et al. Pancreatic cancer. Lancet 2011; 378: 607-620
2 Rubio-Viqueira B, Jimeno A, Cusatis G et al. An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res 2006; 12: 4652-4661
3 Hidalgo M, Amant F, Biankin AV et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov 2014; 4: 998-1013
4 Garrido-Laguna I, Uson M, Rajeshkumar NV et al. Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer. Clin Cancer Res 2011; 17: 5793-5800
5 Zhao H, Thienpont B, Yesilyurt BT et al. Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks. Elife 2014; 3: e02725
6 Li H, Durbin R. Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics 2010; 26: 589-595
7 McKenna A, Hanna M, Banks E et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20: 1297-1303
8 Futreal PA, Coin L, Marshall M et al. A census of human cancer genes. Nat Rev Cancer 2004; 4: 177-183
9 Scheinin I, Sie D, Bengtsson H et al. DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly. Genome Res 2014; 24: 2022-2032
10 Van Lo P, Nordgard SH, Lingjaerde OC et al. Allele-specific copy number analysis of tumors. Proc Natl Acad Sci USA 2010; 107: 16910-16915
11 Garcia-Dios DA, Lambrechts D, Coenegrachts L et al. High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma. Gynecol Oncol 2013; 128: 327-334
12 Aronesty E. Comparison of sequencing utility programs. The Open Bioinformatics Journal 2013; 7: 1-8
13 Waddell N, Pajic M, Patch AM et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518: 495-501
14 Garralda E, Paz K, Lopez-Casas PP et al. Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment. Clin Cancer Res 2014; 20: 2476-2484
15 Delitto D, Pham K, Vlada AC et al. Patient-derived xenograft models for pancreatic adenocarcinoma demonstrate retention of tumor morphology through incorporation of murine stroma elements. Am J Pathol 2015; 185: 1297-1303
16 Akashi Y, Oda T, Ohara Y et al. Histological advantages of the tumor graft. Pancreas 2015; 42: 1275-1282
17 Walters DM, Stokes JB, Adair SJ et al. Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens. PLoS One 2013; 8: e77065