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

Mari Kogiso, Lin Qi, Holly Lindsay, Yulun Huang, Xiumei Zhao, Zhigang Liu, Frank K. Braun, Yuchen Du, Huiyuan Zhang, Goeun Bae, Sibo Zhao, Sarah G. Injac, Mary Sobieski, David Brunell, Vidya Mehta, Diep Tran, Jeffrey Murray, Patricia A. Baxter, Xiao Jun Yuan, Jack M. SuAdekunle Adesina, Laszlo Perlaky, Murali Chintagumpala, D. Williams Parsons, Ching C. Lau, Clifford C. Stephan, Xinyan Lu, Xiao Nan Li*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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 in vivo 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 in vivo 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 CDKN2A shifted from disomy chromosome 9 to trisomy chromosome 9; and BRAF V600E mutation allele frequency increased (from 28% in patient tumor to 67% in passage III xenografts). In vitro drug screening identified 2/7 BRAF V600E inhibitors and 2/9 BRAF 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, CDKN2A homozygous deletion in trisomy chromosome 9 cells, and BRAF V600E mutation as candidate drivers of tumor progression in the PXA xenografts.

Original languageEnglish (US)
Pages (from-to)87455-87471
Number of pages17
JournalOncotarget
Volume8
Issue number50
DOIs
StatePublished - Jan 1 2017

Keywords

  • BRAF V600E
  • CDKN2A
  • Cancer stem cell
  • Low grade glioma
  • Orthotopic xenograft

ASJC Scopus subject areas

  • Oncology

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    Kogiso, M., Qi, L., Lindsay, H., Huang, Y., Zhao, X., Liu, Z., Braun, F. K., Du, Y., Zhang, H., Bae, G., Zhao, S., Injac, S. G., Sobieski, M., Brunell, D., Mehta, V., Tran, D., Murray, J., Baxter, P. A., Yuan, X. J., ... Li, X. N. (2017). 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. Oncotarget, 8(50), 87455-87471. https://doi.org/10.18632/oncotarget.20713