Xenotransplantation of pediatric low grade gliomas confirms the enrichment of BRAF V600E mutation and preservation of CDKN2A deletion in a novel orthotopic xenograft mouse model of progressive pleomorphic xanthoastrocytoma

• Published in: Oncotarget Vol. 8; no. 50; pp. 87455 - 87471
• Main Authors: Kogiso, Mari, Qi, Lin, Lindsay, Holly, Huang, Yulun, Zhao, Xiumei, Liu, Zhigang, Braun, Frank K, Du, Yuchen, Zhang, Huiyuan, Bae, Goeun, Zhao, Sibo, Injac, Sarah G, Sobieski, Mary, Brunell, David, Mehta, Vidya, Tran, Diep, Murray, Jeffrey, Baxter, Patricia A, Yuan, Xiao-Jun, Su, Jack M, Adesina, Adekunle, Perlaky, Laszlo, Chintagumpala, Murali, Parsons, D Williams, Lau, Ching C, Stephan, Clifford C, Lu, Xinyan, Li, Xiao-Nan
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.10.2017
• Subjects: Research Paper; BRAF V600E; orthotopic xenograft; cancer stem cell; CDKN2A; low grade glioma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.20713

To identify cellular and molecular changes that driver pediatric low grade glioma (PLGG) progression, we analyzed putative cancer stem cells (CSCs) and evaluated key biological changes in a novel and progressive patient-derived orthotopic xenograft (PDOX) mouse model. Flow cytometric analysis of 22 PLGGs detected CD133 (<1.5%) and CD15 (20.7 ± 28.9%) cells, and direct intra-cranial implantation of 25 PLGGs led to the development of 1 PDOX model from a grade II pleomorphic xanthoastrocytoma (PXA). While CSC levels did not correlate with patient tumor progression, neurosphere formation and tumorigenicity, the PDOX model, IC-3635PXA, reproduced key histological features of the original tumor. Similar to the patient tumor that progressed and recurred, IC-3635PXA also progressed during serial subtransplantations (4 passages), exhibiting increased tumor take rate, elevated proliferation, loss of mature glial marker (GFAP), accumulation of GFAP /Vimentin cells, enhanced local invasion, distant perivascular migration, and prominent reactive gliosis in normal mouse brains. Molecularly, xenograft cells with homozygous deletion of shifted from disomy chromosome 9 to trisomy chromosome 9; and V600E mutation allele frequency increased (from 28% in patient tumor to 67% in passage III xenografts). drug screening identified 2/7 V600E inhibitors and 2/9 inhibitors that suppressed cell proliferation. In summary, we showed that PLGG tumorigenicity was low despite the presence of putative CSCs, and our data supported GFAP /Vimentin cells, homozygous deletion in trisomy chromosome 9 cells, and mutation as candidate drivers of tumor progression in the PXA xenografts.