Oncotarget

Research Papers:

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. Su, Adekunle Adesina, Laszlo Perlaky, Murali Chintagumpala, D. Williams Parsons, Ching C. Lau, Clifford C. Stephan, Xinyan Lu and Xiao-Nan Li _

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Oncotarget. 2017; 8:87455-87471. https://doi.org/10.18632/oncotarget.20713

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Abstract

Mari Kogiso1,*, Lin Qi1,*, Holly Lindsay1,*, Yulun Huang1,2,*, Xiumei Zhao1,3, Zhigang Liu1,4, Frank K. Braun1, Yuchen Du1, Huiyuan Zhang1, Goeun Bae5, Sibo Zhao1, Sarah G. Injac1, Mary Sobieski5, David Brunell5, Vidya Mehta6, Diep Tran6, Jeffrey Murray7, Patricia A. Baxter1, Xiao-Jun Yuan8, Jack M. Su1, Adekunle Adesina6, Laszlo Perlaky1, Murali Chintagumpala1, D. Williams Parsons1, Ching C. Lau1, Clifford C. Stephan5, Xinyan Lu9 and Xiao-Nan Li1

1Department of Pediatrics, Baylor College of Medicine, Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX, USA

2Department of Neurosurgery, The First Affiliated Hospital, Soochow University, Suzhou, China

3Department of Ophthalmology, First Affiliated Hospital of Harbin, Medical University, Harbin, China

4Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

5Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M College of Medicine, Houston, TX, USA

6Department of Pathology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

7Department of Hematology and Oncology, Cook Children’s Medical Center, Fort Worth, TX, USA

8Department of Hematology and Oncology, Xinhua Children’s Hospital, Shanghai, China

9Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

*These authors have contributed equally to this study

Correspondence to:

Xiao-Nan Li, email: [email protected]

Keywords: low grade glioma, orthotopic xenograft, cancer stem cell, BRAF V600E, CDKN2A

Received: March 16, 2017     Accepted: August 15, 2017     Published: September 08, 2017

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.


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