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

Berta Segura-Collar, María Garranzo-Asensio, Beatriz Herranz, Esther Hernández-SanMiguel, Bárbara. S. Casas, Ander Matheu, Ángel Pérez-Núñez, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Laín, Verónica Palma, Ricardo Gargini, Pilar Sánchez-Gómez
2020 · doi:10.1101/2020.09.21.306134
preprint OA: closed
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Abstract

Rationale Glioma 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. Methods We 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. Results We 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. Conclusions The 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 . 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.

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