BT-08 * AUTOPSY DERIVED ORTHOTOPIC XENOGRAFT (ADOX) MOUSE MODELS FOR TERMINAL PEDIATRIC BRAIN TUMORS

Abstract

Accumulating evidences suggest that recurrent tumors may acquire genetic abnormalities different from their treatment naive counterparts. Since surgery is rarely an option for terminal brain tumors, autopsy is frequently the only chance to obtain therapy resistant tumor tissues. To determine and if (some) tumor cells can survival postmortem anoxia/starvation and to identify the seed cells that repopulate orthotopic xenograft tumors, we collected 29 autopsied brain tumors, including 15 DIPGs, 7 GBMs, 4 medulloblastomas (MB), 2 ependymomas and 1 ATRT, and made the following discoveries. i) A small fraction of tumor cells exhibited strong survival capacity and remained viable, ranging from 0.5%-40% (13.5% ± 10.9%), in tumors harvested 5-72 hrs (31.2 ± 25 hrs) after patients' death. ii) Many autopsied tumor cells stayed alive for short terms in culture and one pair of permanent lines (monolayer and neurosphere) were established from a GBM tumor. iii) Direct implantation of tumor cells into the brains of SCID mice led to the formation of orthotopic xenograft tumors in 17 of 22 tumors. 8 of the 17 autopsy derived orthotopic (ADOX) models have been subtransplanted in mouse brains for >3 times (5 DIPGs and 1 each of GBM, MB and ATRT). These ADOX tumors replicated histopathological features and genetic/genomic abnormalities of the patient tumors. iv) Time course analysis of putative cancer stem cells (CD133, CD15, CD24/CD44, CD57, CD117) identified CD57+ tumor cells as the most abundant viable subpopulation in the autopsied tumors, and their fractions increased in the ADOX tumors during serial subtransplantations. v) Purified CD57+ cells were able to form orthotopic xenografts, establishing their role as cancer stem cells. In conclusion, we have established a novel panel of ADOX mouse models for terminal brain tumors, and identified CD57 as a new marker for therapy-resistant cells that exhibited extraordinary survival and tumorigenic capabilities.