PCM-05AUTOPSY-DERIVED ORTHOTOPIC XENOGRAFT MOUSE MODELS OF TERMINAL PEDIATRIC BRAIN TUMORS

PCM-05. AUTOPSY-DERIVED ORTHOTOPIC XENOGRAFT MOUSE MODELS OF TERMINAL PEDIATRIC BRAIN TUMORS Lin Qi1, Patricia Baxter1, Mari Kogiso1, Yuchen Du1, Holly Lindsay1, Zhigang Liu1, Frank K. Braun1, Xiumei Zhao1, Yujing Zhang1, Jack Su1, Adekunle Adesina2, Xiaojun Yuan3, Andrew W. Walter4, Jeffrey Murray5, Rene McNall-Knapp6, Javad Nazarian7, D. Will Parsons1, MuraliChintagumpala1, andXiao-Nan Li1; Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Xinhua Children’s Hospital, Shanghai, China; Department of Pediatrics Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Cook Children’s Hospital, Fort Worth, TX, USA; OU Medical Center in Pediatric Hematology-Oncology, Oklahoma City, OK, USA; 7The Children’s Research Institute, Washington, DC, USA BACKGROUND: Accumulating evidence suggests significant biological differences between treatment-naive tumorsand therapy-resistant samplesobtained at relapse or autopsy. Despite the need for animal models of terminal brain tumors, it remains unknown if autopsied tumors can be successfully used for model development. METHODS: We collected 29 autopsied brain tumors, including 15 diffuse intrinsic pontine gliomas, 7 glioblastomas, and 4 medulloblastomas. 0.5-40% of tumor cells (average 13.5+10.9%) exhibited strong survival capacity and remained viable 5-72 hours (average 31.2+25 hours) after patients’ death, with no correlation between cell viability and time between death and xenograft implantation (r 1⁄4 0.17). RESULTS: Implantation of tumor cells into matched locations in SCID mice led to formation of xenograft tumors in 17/22 tumors (7 tumors pending). 8/17 autopsyderived orthotopic xenograft (ADOX) models have been sub-transplanted in mouse brains more than 3 times. Detailed characterization confirmed that the ADOX models replicated the histopathological features and genomic abnormalities of the patient tumors. To identify the cellular origin of surviving patient tumor cells that propagated ADOX model formation, flow cytometry analysis of putative cancer stem cells was performed. CD57+ tumor cells were the most abundant sub-populations in the autopsied tumors, and their fractions increased over serial sub-transplantations. Additionally, CD57+ cells alone were able to form orthotopic xenografts, establishing their role as cancer stem cells. CD57 can now be considered a new marker of therapy-resistant cells with extraordinary survival and tumorigenic (TREST) capabilities. CONCLUSION: Our novel panel of ADOX models will facilitate biological studies and pre-clinical drug screening of therapy-resistant pediatric brain tumors. Neuro-Oncology 18:iii139–iii144, 2016. doi:10.1093/neuonc/now080.5 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.