Brain tumor glioblastoma remain one of the most aggressive malignancy, with no change in 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 resistant 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 state is tightly regulated by the GSC microenvironment, named GSC niches. 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 GSC niches, where mesenchymal stem/stromal cells (MSCs) are comprising a significant fraction of the cell types present. However, the effects of specific stromal cells, such as MSCs, on the GSC phenotype in niches have been poorly investigated in comparison with other types of stromal cells.

Objectives

Objective of the research project is to reveal new mechanisms of glioblastoma therapeutic resistance and specifically to elucidate the role of interactions between mesenchymal stem cells (MSCs) and glioblastoma stem cells (GSCs) in tumors. The specific aims are:

1) to determine whether MSCs as a cellular component of patient-derived organotypic multicellular spheroids are associated with GSCs and glioblastoma cell responses to treatment and patient outcome,

2) to compare the responses to therapy between patient-derived GSCs alone and GSCs in co-cultures with MSCs in in vitro and in vivo models, and

3) to elucidate mechanisms of MSC-altered GSC responses to treatment by analyzing cellular processes and phenotype changes.

We will provide novel information if MSCs, as “good” or “bad guys” in glioblastoma progression after standard treatment.

Relevance and potential impact of results

The proposed project addresses the problem of glioblastoma therapy resistance that results in tumor recurrence and early death of patients. 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 efficiently in glioblastoma tumors.

The feasibility of the project is facilitated by the project of European Programme of Cross-Border Cooperation for Slovenia-Italy Interreg TRANS-GLIOMA  and GLIOBANK, established during this project.

We are open for collaborations, if you’re interested please contact dr. Barbara Breznik.