The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

Abstract

RationaleGlioma progression is driven by the induction of vascular alterations but how the tumor genotype influence these changes is still a pending issue. We propose to study the underlying mechanisms by which the genetic changes in isocitrate dehydrogenase 1/2 (IDH1/2) and epidermal growth factor receptor (EGFR) genes establish the different vascular profiles of gliomas. MethodsWe stratified gliomas based on the genetic status of IDH1/2 and EGFR genes. For that we used in silico data and a cohort of 93 glioma patients, where we analyzed the expression of several transcripts and proteins. For the in vitro and in vivo studies, we used a battery of primary glioblastoma cells derived from patients, as well as novel murine glioma cell lines expressing wild-type or mutant EGFR. In these models, the effect of the small molecule ibrutinib or the downregulation of CD248 and SOX9 was evaluated to establish a molecular mechanism. ResultsWe show that IDH1/2 mutations associate with a normalized vasculature. By contrast, EGFR mutations stimulate the plasticity of glioma cells and their capacity to function as pericytes in a bone-marrow and X-linked (BMX)/SOX9 dependent manner. The presence of tumor-derived pericytes stabilize the profuse vasculature and confers a growth advantage to these tumors, although they render them sensitive to pericyte-targeted molecules. Wild-type/amplified EGFR gliomas are enriched in blood vessels too, but they show a highly disrupted blood-brain-barrier due to a decreased BMX/SOX9 activation and pericyte coverage. This leads to poor nutrient supply, necrosis and hypoxia. ConclusionsThe function of tumor-derived pericytes delimitates two distinct and aggressive vascular phenotypes in IDH1/2 wild-type gliomas. Our results lay the foundations for a vascular dependent stratification of gliomas and suggest different therapeutic vulnerabilities depending on the genetic status of EGFR. O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/306134v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@64bff5org.highwire.dtl.DTLVardef@76711aorg.highwire.dtl.DTLVardef@1fb8306org.highwire.dtl.DTLVardef@1570f51_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. Schematic view of IDH and EGFR function in the regulation of glioma microenvironment. Mutant IDH gliomas express low levels of angiogenic molecules and have a vasculature reminiscent of normal tissue. EGFR mutations drive glioma growth by promoting tumor-to-pericyte transdifferentiation and vascular stabilization in a BMX-SOX9 dependent way. Leaky vessels with hypoxia and necrosis characterize tumors overexpressing the wild-type isoform of the receptor. These phenotypes determine the response to therapy of the different IDH wild-type gliomas. C_FIG