1. Patient-derived tumor organoids mimic treatment-induced DNA damage response in glioblastomaBernarda Majc, Anamarija Habič, Marta Malavolta, Miloš Vittori, Andrej Porčnik, Roman Bošnjak, Jernej Mlakar, Alenka Matjašič, Andrej Zupan, Marija Skoblar Vidmar, Tamara Lah Turnšek, Aleksander Sadikov, Barbara Breznik, Metka Novak, 2024, original scientific article Abstract: Glioblastoma (GB) is the most common primary malignant brain tumor, characterized by resistance to therapy. Despite aggressive treatment options, GB remains an incurable disease. Invasiveness and heterogeneity are key GB features that cannot be studied in preclinical in vitro models. In this study, we investigated the effects of standard therapy using patient-derived GB organoids (GBOs). GBOs reflect the complexity and heterogeneity of the original tumor tissue. No significant effect on GBO viability or invasion was observed after irradiation and temozolomide treatment. E3 ubiquitin-protein ligase (MDM2), cyclin-dependent kinase inhibitor 1A (CDKN1A), and the serine/threonine kinases ATM and ATR were upregulated at the gene and protein levels after treatment. Our results show that the p53 pathway and DNA-damage response mechanisms were triggered, suggesting that GBOs recapitulate GB therapy resistance. GBOs thus provide a highly efficient platform to assess the specific responses of GB patients to therapy and to further explore therapy resistance.
Keywords: cellular physiology, cellular toxicology, in vitro toxicology including 3D culture, technical aspects of cell biology, cancer
Published in DiRROS: 09.09.2024; Views: 149; Downloads: 84
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2. Dynamic expression of 11 miRNAs in 83 consecutive primary and corresponding recurrent glioblastoma : correlation to treatment, time to recurrence, overall survival and MGMT methylation statusBoštjan Matos, Emanuela Boštjančič, Alenka Matjašič, Mara Popović, Damjan Glavač, 2018, original scientific article Abstract: Background. Glioblastoma (GBM) is the most common and the most malignant glioma subtype. Among numerous genetic alterations, miRNAs contribute to pathogenesis of GBM and it is suggested that also to GBM recurrence and resistance to therapy. Based on publications, we have selected 11 miRNAs and analyzed their expression in GBM. We hypothesized that selected miRNAs are differentially expressed and involved in primary as well as in recurrent GBM, that show significant expressional differences when different treatment options are in question, and that are related to certain patients and tumor characteristics. Patients and methods. Paraffin embedded tissues, obtained from primary and corresponding recurrent tumor from 83 patients with primary GBM were used. Eleven miRNAs ( miR-7, miR-9, miR-15b, miR-21, miR-26b, miR-124a, miR-199a, let-7a, let-7b, let-7d, and let-7f ) were selected for qPCR expression analysis. For patients who received temozolamide (TMZ) as chemotherapeutic drug, O6-methylguanine-DNA methyltransferase (MGMT) methylation status was defined using the methyl-specific PCR. Results. There was a significant change in expression of miR-7, miR-9, miR-21, miR-26b, mirR-124a, miR-199a and let- 7f in recurrent tumor compared to the primary. In recurrent tumor, miR-15b, let-7d and let-7f significantly changed comparing both treatment options. We also observed difference in progression free survival between patients that received radiotherapy and patients that received radiotherapy and chemotherapy, and longer survival for patients who received chemotherapy after second surgery compared to not treated patients. miR-26b showed correlation to progression free survival and let-7f to overall survival. We did not find any expression difference between the tumors with and without methylated MGMT. Conclusions. Our data suggest that analyzed miRNAs may not only contribute to pathogenesis of primary GBM, but also to tumor progression and its recurrence. Moreover, expression of certain miRNAs appears to be therapy- dependent and as such they might serve as additional biomarker for recurrence prediction and potentially predict a therapy-resistance.
Keywords: glioblastoma, radiotherapy, chemotherapy
Published in DiRROS: 02.07.2024; Views: 255; Downloads: 147
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3. Expression of LOC285758, a potential long non-coding biomarker, is methylation- dependent and correlates with glioma malignancy gradeAlenka Matjašič, Mara Popović, Boštjan Matos, Damjan Glavač, 2017, original scientific article Abstract: Background. Identifying the early genetic drivers can help diagnose glioma tumours in their early stages, before becoming malignant. However, there is emerging evidence that disturbance of epigenetic mechanisms also con- tributes to cell's malignant transformation and cancer progression. Long non-coding RNAs are one of key epigenetic modulators of signalling pathways, since gene expression regulation is one of their canonical mechanisms. The aim of our study was to search new gliomagenesis-specific candidate lncRNAs involved in epigenetic regulation. Patients and methods. We used a microarray approach to detect expression profiles of epigenetically involved lncRNAs on a set of 12 glioma samples, and selected LOC285758 for further qPCR expression validation on 157 glioma samples of different subtypes. To establish if change in expression is a consequence of epigenetic alterations we determined methylation status of lncRNA's promoter using MS-HRM. Additionally, we used the MLPA analysis for de- termining the status of known glioma biomarkers and used them for association analyses. Results. In all glioma subtypes levels of LOC285758 were significantly higher in comparison to normal brain reference RNA, and expression was inversely associated with promoter methylation. Expression substantially differs between astrocytoma and oligodendroglioma, and is elevated in higher WHO grades, which also showed loss of methylation. Conclusions. Our study revealed that lncRNA LOC285758 changed expression in glioma is methylation-dependent and methylation correlates with WHO malignancy grade. Methylation is also distinctive between astrocytoma I-III and other glioma subtypes and may thus serve as an additional biomarker in glioma diagnosis.
Keywords: glioma, epigenetics, methylation
Published in DiRROS: 03.06.2024; Views: 356; Downloads: 247
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4. Minimalno invazivni diagnostični pristopi pri primarnih možganskih tumorjih z uporabo prosto cirkulirajočih nukleinskih kislinMarija Skoblar Vidmar, Jernej Mlakar, Uroš Smrdel, Alenka Matjašič, Jože Pižem, Andrej Zupan, 2021, published scientific conference contribution Keywords: tekočinska biopsija, onkološko zdravljenje, možganski tumorji
Published in DiRROS: 04.04.2022; Views: 929; Downloads: 328
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