Role of serine-threonine phosphatases in temozolomide resistance of glioblastoma Group Vassella Glioblastoma is the most common and most aggressive primary malignant brain tumour in adults. We followed an unbiased approach for the identification of microRNAs that are most efficient at conferring resistance to the alkylating agent temozolomide in glioblastoma cells. We identified miR-19b and its direct target PPP2R5E, a regulatory subunit of the PP2A serine phosphatase, in temozolomide response in glioblastoma. The mechanism was attributed to the induction of DNA damage via increased nuclear ROS production, ultimately leading to elevated ROS-mediated senescence and ferroptosis in cells with attenuated miR-19b/PPP2R5E expression. This project has been supported by the Swiss National Science Foundation. Screening for microRNAs conferring temozolomide resistance in glioblastoma cell lines
Nonsense-mediated mRNA decay, the achilles heel of recurrent glioblastoma? Group Vassella We conducted CRISPR/CAS interference library screens and identified SMG1, implicated in an evolutionarily conserved RNA quality control pathway - the nonsense-mediated mRNA decay (NMD) pathway. NMD leads to the degradation of transcripts containing premature stop codons, often occurring after temozolomide treatment. NMD may influence the mechanisms employed by tumour cells to repair DNA damage caused by temozolomide treatment. Hence, we hypothesise that the enhanced temozolomide response is due to reduced DNA repair capacity in SMG1-attenuated glioblastoma cells. The aim of this work is to further investigate the mechanisms leading to an enhanced temozolomide response in glioblastoma cells with attenuated SMG1. Since NMD efficiently suppresses truncated proteins, which are highly immunogenic, we hypothesise that SMG1 inhibition in temozolomide-resistant, recurrent glioblastoma may elicit tumour inflammation. Hence, we expect that NMD improves the treatment response to immune checkpoint inhibitors. This work is currently supported by the Swiss Cancer League. Heat map analysis of recurrent glioblastoma
Identification of synergistically acting miRNA-regulated networks for modulating therapy response in glioblastoma Group Vassella This project investigates the mechanisms driving temozolomide (TMZ) resistance in adult recurrent IDH-wildtype glioblastomas, with a focus on synergistic microRNA (miRNA) networks that contribute to tumor relapse. Using a single-center paired cohort of good TMZ responders (relapse interval >1 year), we identified 13 miRNAs with highly correlated expression in the relapsed tumors. These miRNA hubs are hypothesized to act synergistically, regulating key resistance pathways such as DNA damage repair, tumor plasticity, and cell survival. Additionally, our analysis highlights their role in modulating oncogenic pathways, including Wnt and TGF-β signaling, which drive stemness, EMT, and adaptive resistance. Importantly, this study represents the largest miRNA cohort profiled to date. We are currently investigating the extent and specific perturbations of miRNA regulatory hubs in cases with short relapse intervals and poor therapy responses, aiming to identify miRNAs with prognostic and predictive value. Our established patient-derived glioblastoma stem cell models will be utilized to investigate whether these dynamic miRNA networks influence short-term and long-term therapeutic responses. By targeting these networks, we aim to sensitize glioblastoma stem cells to TMZ in vitro and in vivo, paving the way for miRNA-based therapies to overcome resistance. This work is supported by Krebsliga Bern and Stiftung Für Klinisch-Experimentelle Tumorforschung SKET (to E. Kashani).
Clinical, pathological and molecular characterization of adult medulloblastomas for targeted therapy: a multicenter cohort study including primary and relapse cases Group Vassella Medulloblastomas are the most common aggressive pediatric brain tumors, molecularly defined by different groups and subgroups. Although medulloblastoma is a rare disease, it has been also described in postpubertal and adult patients. The lack of studies exclusively on adult medulloblastomas means that the therapeutic approach in these patients is mainly based on existing data from studies on pediatric medulloblastomas. For these reasons and given that adult patients do not have a satisfactory clinical outcome after therapy, we would like to study a large cohort of adult medulloblastomas and medulloblastoma relapses on a clinical, pathological and molecular level in order to further characterize the biology of these tumors for developing a targeted therapy adapted to their molecular profile. Classic histomorphology of an adult medulloblastoma
