Projects / Programmes
The impact of mesenchymal stem cells on glioblastoma therapeutic resistance
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
brain tumor, glioblastoma, therapeutic resistance, tumor microenvironment, stem cells, niche, 3D cellular models, zebrafish embryos
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
36319 |
PhD Barbara Breznik |
Biology |
Head |
2019 - 2022 |
0 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0105 |
National Institute of Biology |
Ljubljana |
5055784 |
0 |
Abstract
Glioblastoma remains one of the most aggressive malignancies without improvement of the standard treatment for almost 20 years. Standard therapy may reduce the tumor in size, make it even too small to detect, and contain the disease for a few months by killing susceptible cells, but the surviving cells are therapy resistant. This subpopulation of glioblastoma cells in tumors have characteristic expression of stem cell-related genes and are named glioblastoma stem cells (GSCs). GSCs are slowly-dividing cells expressing DNA repair mechanisms and multidrug resistance mechanisms that enable survival of GSCs after radio- and chemotherapy causing regrowth of the tumor. In vivo, the GSC phenotype is tightly regulated by the GSC microenvironment, specific micro-anatomical regions within the tumor, named GSC niches. There is increasing evidence of a key role of complex interactions between cancer cells and non-cancerous stromal cells in glioblastoma therapy resistance, in particular in GSC niches, where mesenchymal stem cells (MSCs) are a significant fraction of the cell types present. Unraveling molecular regulation of the GSC phenotype in their niches is crucial for the development of novel therapeutics directed against GSCs, but effects of specific stromal cells, such as MSCs, on the GSC phenotype have been poorly investigated in comparison with that of other types of stromal cells. MSCs have a significant role in glioblastoma progression after their engraftment into the glioblastoma microenvironment. It has been demonstrated that radiotherapeutic treatment of GSCs and glioblastoma cells even increases the tropism of MSCs towards glioblastoma cells and tumors. Recent studies and our unpublished results suggest that higher amounts of MSCs in tumor tissues are associated with poor outcome of glioblastoma patients and that MSCs decrease the sensitivity of GSCs to treatment. Cellular interactions and their impact on glioblastoma resistance have to be studied in appropriate models, which as closely as possible resemble the conditions in vivo. In our experimental approach, organotypic multicellular spheroids will be used, which recapitulate the original heterogeneity of tumors containing differentiated cancer cells, cancer stem cells and various types of stromal cells. Besides, the xenotransplantation zebrafish embryo model will be applied to study glioblastoma progression on the basis of its simplicity and its potential for high-throughput quantification of cellular processes.
The main objective of the proposed research project is to reveal new mechanisms of glioblastoma therapeutic resistance and, specifically, to elucidate the role of interactions between MSCs and GSCs in GSC niches before and after irradiation, chemotherapy or both in different in vitro and in vivo experimental setups. In the proposed research project, we aim to explore:
a) whether the presence and quantity of MSCs in patient-derived organotypic multicellular spheroids is associated with glioblastoma cell and GSC sensitivity to treatment and patient survival,
b) how MSC-GSC interactions within GSC niches affect GSC sensitivity to irradiation and temozolomide in vitro and in vivo,
c) what are the biological mechanisms of MSC-altered GSC responses to therapy, and
d) which paracrine factors mediate interactions between MSCs and GSCs within GSC niches after the treatment.
To reveal the role of MSCs in GSC defense mechanisms against therapeutics, we will provide novel information on pro- and/or anti-GSC activity of MSCs, as “good” or “bad" guys in glioblastoma progression after standard treatment. The findings obtained in the proposed research project will thus deepen the knowledge of glioblastoma pathobiology and will give novel insights into complex mechanisms of glioblastoma treatment resistance. Consequently, our findings will provide a basis for further innovative approaches to target glioblastoma stem cells successfully in glioblastoma tumors.
Significance for science
The proposed project addresses the problem of therapeutic resistance of glioblastoma that results in tumor recurrence and early death of patients. New treatments that take into consideration the complexity of glioblastoma are needed and require a deep understanding of the basis biology that drives the disease. There is increasing evidence of a key role of complex interactions between cancer cell and non-cancerous stromal cells in glioblastoma therapy resistance, in particular in glioblastoma stem cell niches, where mesenchymal stem cells are a significant fraction of the cell types present. To reveal the role of mesenchymal stem cells in glioblastoma stem cell defense mechanisms against therapeutics, we will provide novel information on pro- and/or anti-glioblastoma stem cell activity of mesenchymal stem cells, as “good” or “bad" guys in glioblastoma progression after standard treatment. Moreover, our findings will have implications in translational oncology for the development of novel therapeutic possibilities by identifying key players in therapeutic resistance of glioblastoma stem cells.
Mesenchymal stem cells-based therapeutic strategies for glioblastoma has become an important focus of research, but the role and function of mesenchymal stem cells in glioblastoma are still largely unknown. Our experimental approach enables elucidation of the role of mesenchymal stem cells within glioblastoma stem cell niches in therapeutic resistance of glioblastoma in vitro as well as in vivo. Our focus will be in particular on interactions between mesenchymal stem cells and glioblastoma stem cells, that affect responses of glioblastoma stem cells to irradiation and chemotherapy and what the biological mechanisms are.
To the best of our knowledge, this will be the first study to address the role and functions of mesenchymal stem cells in glioblastoma responses to radio- and chemotherapy. Moreover, we will be the first to address these problems in patent-derived organotypic multicellular spheroids and zebrafish embryo models. The findings obtained in the proposed research project will thus deepen our understanding of glioblastoma pathobiology and will give novel insights into complex mechanisms of glioblastoma treatment resistance. Consequently, our findings will provide a basis for further innovative approaches to target glioblastoma stem cells successfully in glioblastoma tumors.
Significance for the country
The proposed project addresses the problem of therapeutic resistance of glioblastoma that results in tumor recurrence and early death of patients. New treatments that take into consideration the complexity of glioblastoma are needed and require a deep understanding of the basis biology that drives the disease. There is increasing evidence of a key role of complex interactions between cancer cell and non-cancerous stromal cells in glioblastoma therapy resistance, in particular in glioblastoma stem cell niches, where mesenchymal stem cells are a significant fraction of the cell types present. To reveal the role of mesenchymal stem cells in glioblastoma stem cell defense mechanisms against therapeutics, we will provide novel information on pro- and/or anti-glioblastoma stem cell activity of mesenchymal stem cells, as “good” or “bad" guys in glioblastoma progression after standard treatment. Moreover, our findings will have implications in translational oncology for the development of novel therapeutic possibilities by identifying key players in therapeutic resistance of glioblastoma stem cells.
Mesenchymal stem cells-based therapeutic strategies for glioblastoma has become an important focus of research, but the role and function of mesenchymal stem cells in glioblastoma are still largely unknown. Our experimental approach enables elucidation of the role of mesenchymal stem cells within glioblastoma stem cell niches in therapeutic resistance of glioblastoma in vitro as well as in vivo. Our focus will be in particular on interactions between mesenchymal stem cells and glioblastoma stem cells, that affect responses of glioblastoma stem cells to irradiation and chemotherapy and what the biological mechanisms are.
To the best of our knowledge, this will be the first study to address the role and functions of mesenchymal stem cells in glioblastoma responses to radio- and chemotherapy. Moreover, we will be the first to address these problems in patent-derived organotypic multicellular spheroids and zebrafish embryo models. The findings obtained in the proposed research project will thus deepen our understanding of glioblastoma pathobiology and will give novel insights into complex mechanisms of glioblastoma treatment resistance. Consequently, our findings will provide a basis for further innovative approaches to target glioblastoma stem cells successfully in glioblastoma tumors.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
Interim report
