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.>
