Patient-derived tumor organoids mimic treatment-induced DNA damage response in glioblastoma
Bernarda 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
Affiliations
Bernarda Majc
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia; Jožef Stefan International Postgraduate School, Nanosciences and Nanotechnologies, 1000 Ljubljana, Slovenia
Anamarija Habič
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia; Jožef Stefan International Postgraduate School, Nanosciences and Nanotechnologies, 1000 Ljubljana, Slovenia
Marta Malavolta
University of Ljubljana, Faculty of Computer and Information Science, 1000 Ljubljana, Slovenia
Miloš Vittori
University of Ljubljana, Biotechnical Faculty, Department of Biology, 1000 Ljubljana, Slovenia
Andrej Porčnik
Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
Roman Bošnjak
Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
Jernej Mlakar
Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
Alenka Matjašič
Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
Andrej Zupan
Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
Marija Skoblar Vidmar
Institute of Oncology, University Medical Centre Ljubljana, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
Tamara Lah Turnšek
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
Aleksander Sadikov
University of Ljubljana, Faculty of Computer and Information Science, 1000 Ljubljana, Slovenia
Barbara Breznik
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
Metka Novak
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia; Corresponding author
Summary: 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.
