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Projects / Programmes source: ARIS

Unravelling glioma stem cell niches for novel therapeutic targets in glioblastoma patients

Research activity

Code Science Field Subfield
3.04.00  Medical sciences  Oncology   

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
Glioblastoma, Glioma stem cells, Bone marrow, Hematopoietic stem cells, Niches, C-X-C receptor type 4, Plerixafor, Stromal-derived factor-1?, Hypoxia, Arterioles, Subventricular zone
Evaluation (rules)
source: COBISS
Researchers (15)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  38158  PhD Urban Bogataj  Biology  Researcher  2020 - 2023  37 
2.  36319  PhD Barbara Breznik  Biology  Researcher  2021 - 2023  164 
3.  34354  PhD Urška Dragin Jerman  Oncology  Researcher  2022 - 2023  59 
4.  15873  PhD Mateja Erdani Kreft  Neurobiology  Researcher  2020 - 2023  399 
5.  29297  PhD Katja Kološa  Biology  Researcher  2020 - 2021  38 
6.  07802  PhD Tamara Lah Turnšek  Biology  Retired researcher  2020 - 2022  1,017 
7.  51984  PhD Bernarda Majc  Biology  Researcher  2023  55 
8.  39755  Mateja Mlinar    Technical associate  2022 - 2023  22 
9.  32116  PhD Metka Novak  Biochemistry and molecular biology  Researcher  2020 - 2023  109 
10.  28393  PhD Nataša Resnik  Biochemistry and molecular biology  Researcher  2022 - 2023  87 
11.  11654  PhD Rok Romih  Neurobiology  Researcher  2020 - 2023  243 
12.  33100  PhD Larisa Tratnjek  Neurobiology  Researcher  2020 - 2023  59 
13.  51349  PhD Cornelis J.F. van Noorden  Biology  Head  2020 - 2023  158 
14.  08279  PhD Peter Veranič  Neurobiology  Researcher  2020 - 2023  356 
15.  32060  PhD Miloš Vittori  Biology  Researcher  2020 - 2023  132 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0105  National Institute of Biology  Ljubljana  5055784  13,253 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  45,335 
3.  0481  University of Ljubljana, Biotechnical Faculty  Ljubljana  1626914  65,752 
Abstract
Glioblastoma is the most aggressive and malignant brain tumor with a median overall survival of 20 months after diagnosis after optimal therapy (surgical tumor resection, radiotherapy, temozolomide chemotherapy and magnetic tumor treating fields). Due to outgrowth of the tumor throughout the brain, it is impossible to surgically resect the entire tumor, which results in recurrence of the tumor in patients. In glioblastoma brain tumors, cancer cells with stem cell characteristics have been described, which are called glioma stem cells (GSCs). GSCs are slowly-dividing cells that reside in special microenvironments in the tumor, called GSC niches where they are maintained as slowly-dividing cells and are protected from therapy, as radiotherapy and chemotherapy are directed against dividing cells. Quiescent GSCs escape from the effects of therapy and are held responsible for tumor recurrence in glioblastoma patients. Therefore, our major aim is to mobilize GSCs out of their protective niches to induce GSC differentiation and proliferation and their sensitization to therapy. We have previously demonstrated in human glioblastoma samples that GSC niches are hypoxic and peri-arteriolar and are similar to hematopoietic stem cell (HSC) niches in healthy human bone marrow. GSCs and HSCs are maintained and retained in hypoxic and peri-arteriolar niches in which similar chemoattrative proteins are involved, including the chemoattractant stromal-derived factor-1? and its receptor C-X-C receptor type 4 (CXCR4) which is expressed on the cell surface of GSCs/HSCs. This SDF-1?/CXCR4 axis facilitates homing of CXCR4-positive GSCs/HSCs in SDF-1?-rich niches. In this research proposal, we aim to determine whether GSC niches in glioblastoma tumors are also similar to normal neural stem cell (NSC) niches located in the subventricular zone (SVZ) of the brain which are poorly characterized. This is relevant as glioblastoma cells home in NSC niches in the SVZ where they are protected from radiotherapy. NSC niches in the SVZ-region will be characterized in normal brain samples and in brain samples that contain glioblastoma tumors. In addition, we aim to unravel why arteriolar walls are uniquely associated with GSC niches in glioblastoma tumors and HSC niches in bone marrow and which signalling pathways that are essential for the maintenance of the arteriolar identity are involved in the maintenance of GSC/HSC stemness. From a clinical point of view it is relevant to investigate whether the acquired knowledge about GSCs/HSCs can be used for the development of novel therapeutic treatment strategies. Therefore, we aim to elucidate whether the FDA-approved CXCR4 inhibitor plerixafor can be used to mobilize GSCs out of their protective niches to induce GSC differentiation and proliferation and sensitization to therapy. We expect to achieve GSC sensitization to therapy using plerixafor, as plerixafor treatment can effectively mobilize leukemic stem cells out of HSC niches resulting in their sensitization to chemotherapy. In conclusion, we aim to characterize NSC niches in normal SVZ and in glioblastoma-invaded SVZ. Furthermore, we aim to investigate why arterioles are specifically associated with GSC/HSC niches. Finally, we aim to determine whether plerixafor can be used to sensitize GSCs to standard glioblastoma therapies.
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