The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

Gargini, Ricardo; Segura-Collar, Berta; Herránz, Beatriz; García-Escudero, Ramón; Romero-Bravo, Andrés; Núñez, Felipe J.; García‐Pérez, Daniel; Gutiérrez-Guamán, Jacqueline; Ayuso-Sacido, Angel; Seoane, Joan; Pérez-Núñez, Ángel; Sepúlveda‐Sánchez, Juan Manuel; Hernández-Laín, Aurelio; García‐Escudero, Ramón; Ávila, Jesús; Sánchez-Gómez, Pilar

doi:10.1101/541326

Cited by 3 publications

(5 citation statements)

References 115 publications

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“…Nevertheless, to date it was unknown if different genetic alterations could modulate this transdiferentation process. Results from this study and our recently published data [7] suggest that it is governed by the EGFR/BMX signaling pathway.…”

Section: Discussionsupporting

confidence: 77%

“…IF and IHC staining was performed as previously described [7] using primary and secondary antibodies described in Table S2. For quantification, slides were scanned at 63X or 40X magnification.…”

Section: Inmunofluorescent (If) and Inmunohistochemical (Ihc) Staining And Quantificationmentioning

confidence: 99%

“…Moreover, we have recently described that the microtubule stabilizer TAU/MAPT is induced in IDHmut gliomas and promotes vascular normalization by opposing EGFR signaling [7]. The EGFR gene is amplified in 50 to 60% of IDHwt GBMs and half of these tumors carry the vIII variant (exons 2-7 deletion), which generates a constitutive activation of the receptor´s tyrosine kinase.…”

Section: Introductionmentioning

confidence: 99%

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Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas

et al. 2021

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The extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in the tumor vessels, reinforcing the vascular architecture. Recently, it was revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves chemotherapy efficiency. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here, we show that mutations in EGFR (epidermal growth factor receptor) stimulate the capacity of glioma cells to function as pericytes in a BMX (bone marrow and X-linked)/SOX9 dependent manner. The subsequent activation of PDGFR (platelet derived growth factor receptor beta) in the vessel walls of EGFR mutant gliomas stabilize the vasculature and facilitates the recruitment of immune cells. These changes in the tumor microenvironment confer a growth advantage to the tumors, although it also makes them particularly sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas are enriched in blood vessels too but they show a highly disrupted blood-brain-barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which lead to poor oxygenation, necrosis and hypoxia. Here, we identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relation between the tumor cells and their vascular and immune microenvironment.Our results lay the foundations for a vascular dependent stratification of gliomas and suggest different therapeutic vulnerabilities depending on the genetic status of EGFR, which defines the vascular and the immune landscape of the tumors.

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Section: Discussionsupporting

confidence: 77%

Section: Inmunofluorescent (If) and Inmunohistochemical (Ihc) Staining And Quantificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas

et al. 2021

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“…SVZ-EGFRvIII tumors showed a highly compact growth, whereas in SVZ-EGFRwt/amp tumors cells appeared detached from each other and from the tumor vessels ( Figure 5A). It has been shown that pericytic functions can be performed by the highly plastic glioma stem cells, which acquire mesenchymal and mural cell features (3) in a process regulated by EGFR signaling (6). In agreement with these notions, some tumor cells expressed αSMA in both SVZ glioma models ( Figure 5B).…”

Section: Glioma Derived-pericytes Stabilize the Vasculature In Egfrmusupporting

confidence: 75%

“…IDH mutant (IDHmut) gliomas have smaller BVs and are associated with less hypoxia compared with their wild-type (wt) counterparts (5). Moreover, we have recently described that the microtubule stabilizer TAU/MAPT is induced in IDHmut gliomas and promotes vascular normalization by opposing EGFR signaling (6).…”

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confidence: 99%

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

Segura-Collar

Garranzo‐Asensio

Herránz

et al. 2020

Preprint

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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.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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Netrin-1 in Glioblastoma Neovascularization: The New Partner in Crime?

Vásquez

Sánchez-Gómez

Palma

2021

IJMS

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Glioblastoma (GBM) is the most aggressive and common primary tumor of the central nervous system. It is characterized by having an infiltrating growth and by the presence of an excessive and aberrant vasculature. Some of the mechanisms that promote this neovascularization are angiogenesis and the transdifferentiation of tumor cells into endothelial cells or pericytes. In all these processes, the release of extracellular microvesicles by tumor cells plays an important role. Tumor cell-derived extracellular microvesicles contain pro-angiogenic molecules such as VEGF, which promote the formation of blood vessels and the recruitment of pericytes that reinforce these structures. The present study summarizes and discusses recent data from different investigations suggesting that Netrin-1, a highly versatile protein recently postulated as a non-canonical angiogenic ligand, could participate in the promotion of neovascularization processes in GBM. The relevance of determining the angiogenic signaling pathways associated with the interaction of Netrin-1 with its receptors is posed. Furthermore, we speculate that this molecule could form part of the microvesicles that favor abnormal tumor vasculature. Based on the studies presented, this review proposes Netrin-1 as a novel biomarker for GBM progression and vascularization.

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The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

Cited by 3 publications

References 115 publications

Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas

Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas

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

Netrin-1 in Glioblastoma Neovascularization: The New Partner in Crime?

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