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Permanent URI for this collectionhttps://hdl.handle.net/11443/932
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Item MEOX2 homeobox gene promotes growth of malignant gliomas(OXFORD UNIV PRESS INC, 2022-01-01) Schoenrock, Anna; Heinzelmann, Elisa; Steffl, Bianca; Demirdizen, Engin; Narayanan, Ashwin; Krunic, Damir; Baehr, Marion; Park, Jong-Whi; Schmidt, Claudia; Oezduman, Koray; Pamir, M. Necmettin; Wick, Wolfgang; Bestvater, Felix; Weichenhan, Dieter; Plass, Christoph; Taranda, Julian; Mall, Moritz; Turcan, SevinBackground Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10, and aberrantly activated receptor tyrosine kinase signaling pathways. Previously, we identified Mesenchyme Homeobox 2 (MEOX2), a gene located on chromosome 7, as an upregulated transcription factor in GBM. Overexpressed transcription factors can be involved in driving GBM. Here, we aimed to address the role of MEOX2 in GBM. Methods Patient-derived GBM tumorspheres were used to constitutively knockdown or overexpress MEOX2 and subjected to in vitro assays including western blot to assess ERK phosphorylation. Cerebral organoid models were used to investigate the role of MEOX2 in growth initiation. Intracranial mouse implantation models were used to assess the tumorigenic potential of MEOX2. RNA-sequencing, ACT-seq, and CUT\&Tag were used to identify MEOX2 target genes. Results MEOX2 enhanced ERK signaling through a feed-forward mechanism. We identified Ser(155) as a putative ERK-dependent phosphorylation site upstream of the homeobox-domain of MEOX2. S155A substitution had a major effect on MEOX2 protein levels and altered its subnuclear localization. MEOX2 overexpression cooperated with p53 and PTEN loss in cerebral organoid models of human malignant gliomas to induce cell proliferation. Using high-throughput genomics, we identified putative transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. Conclusions We identified MEOX2 as an oncogenic transcription regulator in GBM. MEOX2 increases proliferation in cerebral organoid models of GBM and feeds into ERK signaling that represents a core signaling pathway in GBM.Item Oncolytic Virus Therapy for Glioblastoma Multiforme Concepts and Candidates(LIPPINCOTT WILLIAMS \& WILKINS, 2012-01-01) Wollmann, Guido; Ozduman, Koray; van den Pol, Anthony N.Twenty years of oncolytic virus development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding-more than 20 viruses have been recognized as potential oncolytic viruses-new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme. So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against glioblastoma multiforme. In this review, we present an overview of viruses that have been developed or considered for glioblastoma multiforme treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of oncolytic virus application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results