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

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.

^* These authors contributed equally.

• 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