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Rooj, Arun

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Rooj

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Arun

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Rooj, Arun
Author's Publications: search.filters.isAuthorOfPublication.aff2ef09-c56c-4729-99e6-2822740554d2

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    MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer
    (Elsevier, 2017) Godlewski, Jakub; Ferrer-Luna, Ruben; Rooj, Arun; Mineo, Marco; Ricklefs, Franz; Takeda, Yuji S.; Nowicki, M. Oskar; Salińska, Elżbieta; Nakano, Ichiro; Lee, Hakho; Weissleder, Ralph; Beroukhim, Rameen; Chiocca, E.; Bronisz, Agnieszka
    Summary Despite the importance of molecular subtype classification of glioblastoma (GBM), the extent of extracellular vesicle (EV)-driven molecular and phenotypic reprogramming remains poorly understood. To reveal complex subpopulation dynamics within the heterogeneous intratumoral ecosystem, we characterized microRNA expression and secretion in phenotypically diverse subpopulations of patient-derived GBM stem-like cells (GSCs). As EVs and microRNAs convey information that rearranges the molecular landscape in a cell type-specific manner, we argue that intratumoral exchange of microRNA augments the heterogeneity of GSC that is reflected in highly heterogeneous profile of microRNA expression in GBM subtypes.
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    Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles
    (American Association for the Advancement of Science, 2018) Ricklefs, Franz L.; Alayo, Quazim; Krenzlin, Harald; Mahmoud, Ahmad; Speranza, Maria C.; Nakashima, Hiroshi; Hayes, Josie L.; Lee, Kyungheon; Balaj, Leonora; Passaro, Carmela; Rooj, Arun; Krasemann, Susanne; Carter, Bob; Chen, Clark C.; Steed, Tyler; Treiber, Jeffrey; Rodig, Scott; Yang, Katherine; Nakano, Ichiro; Lee, Hakho; Weissleder, Ralph; Breakefield, Xandra; Godlewski, Jakub; Westphal, Manfred; Lamszus, Katrin; Freeman, Gordon; Bronisz, Agnieszka; Lawler, Sean; Chiocca, E.
    Binding of programmed death ligand-1 (PD-L1) to programmed cell death protein-1 (PD1) leads to cancer immune evasion via inhibition of T cell function. One of the defining characteristics of glioblastoma, a universally fatal brain cancer, is its profound local and systemic immunosuppression. Glioblastoma has also been shown to generate extracellular vesicles (EVs), which may play an important role in tumor progression. We thus hypothesized that glioblastoma EVs may be important mediators of immunosuppression and that PD-L1 could play a role. We show that glioblastoma EVs block T cell activation and proliferation in response to T cell receptor stimulation. PD-L1 was expressed on the surface of some, but not of all, glioblastoma-derived EVs, with the potential to directly bind to PD1. An anti-PD1 receptor blocking antibody significantly reversed the EV-mediated blockade of T cell activation but only when PD-L1 was present on EVs. When glioblastoma PD-L1 was up-regulated by IFN-γ, EVs also showed some PD-L1–dependent inhibition of T cell activation. PD-L1 expression correlated with the mesenchymal transcriptome profile and was anatomically localized in the perinecrotic and pseudopalisading niche of human glioblastoma specimens. PD-L1 DNA was present in circulating EVs from glioblastoma patients where it correlated with tumor volumes of up to 60 cm3. These results suggest that PD-L1 on EVs may be another mechanism for glioblastoma to suppress antitumor immunity and support the potential of EVs as biomarkers in tumor patients.