Biology subjects

Kögel, D.

Publications and source records attributed to Kögel, D..

3 recordsLinked to original sources

bioRxiv2024

BRAT1 - a new therapeutic target for glioblastoma

Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of protein breast cancer type 1 susceptibility protein (BRCA1)-associated Ataxia telangiectasia mutated (ATM)-activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic analyses further emphasize the role of BRAT1s cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments.

cancer biology↗

bioRxiv2023

Molecular Determinants of Calcitriol Signaling and Sensitivity in Glioma Stem-like Cells

Glioblastoma is the most common primary brain cancer in adults and represents one of the worst cancer diagnosis for the patients. Suffering from a poor prognosis and limited treatment options, tumor recurrences are virtually inevitable. Additionally, treatment resistance is very common for this disease and worsens the prognosis. These and others factors are hypothesized to be largely due to the fact that glioblastoma cells are known to be able to obtain stem-like traits and thereby driving these phenotypes. Recently, we could show that the in vitro and ex vivo treatment of glioblastoma stem-like cells with the hormonally active form of Vitamin D3, Calcitriol (1,25(OH)2-vitamin D3) can block stemness in a subset of cell lines and reduce tumor growth. Here, we expanded our cell panel to over 40 different cultures and can show that, while half of the tested cell lines are sensitive, a quarter can be classified as high-responders. Using genetic and proteomic analysis, we further determined that treatment success can be partially explained by specific polymorphism of the Vitamin D3 receptor and that high-responders display a proteome suggestive of blockade of stemness, as well as migratory potential.

cancer biology↗

bioRxiv2023

Combining organotypic tissue culture with multi-color fluorescence light-sheet microscopy (OTCxLSFM) - a novel tool to study glioma invasion/migration

Glioblastoma is a very aggressive tumor and represents the most common primary brain malignancy. Key characteristics include its high resistance against conventional treatments, such as radio- and chemotherapy and its diffuse tissue infiltration, preventing complete surgical resection. The analysis of migration and invasion processes in a physiological microenvironment allows for enhanced understanding of these processes and can lead to improved therapeutic approaches. Here, we combine two state-of-the-art techniques, adult organotypic brain tissue slice culture (OTC) and light sheet fluorescence microscopy (LSFM) of cleared tissues in a combined method termed OTCxLSFM. Using this methodology, we can show that glioblastoma tissue infiltration can be effectively blocked through treatment with arsenic trioxide, as well as genetic depletion of the tetraspanin, transmembrane receptor CD9. With our analysis-pipeline we gain single-cell level, three-dimensional information, as well as insights into the morphological appearance of the tumor cells.

cancer biology↗