Biology subjects

Sevenich, L.

Publications and source records attributed to Sevenich, L..

4 recordsLinked to original sources

bioRxiv2025

3R-Compliant Murine Ex Vivo Platform for Scalable Brain Cancer Modeling and Drug Screening

Translating in vitro findings into in vivo applications remains a major challenge in brain cancer drug discovery, largely due to inadequate models for assessing neurotoxicity and tumor microenvironment (TME) dynamics. Here, we present a novel, highly modular murine ex vivo platform based on adult neural stem cells (aNSCs), designed for scalable, medium-throughput drug screening and mechanistic studies for brain cancer research. This system integrates progressive 2D and 3D models, including assembled models for tumor migration, cancer core models mimicking tumor localization within neural tissue and advanced cancer core models incorporating immune cells to recapitulate key TME interactions. With high reproducibility, defined cell composition and rapid formation within 72 hours, these assembloids provide a translationally relevant and ethical alternative to animal models. Aligned with 3R principles, this platform bridges the gap between in vitro and in vivo studies, offering a powerful tool for innovating brain cancer drug discovery.

cancer biology↗

bioRxiv2024

Modulation of the ATP-adenosine signaling axis combined with radiotherapy facilitates anti-cancer immunity in brain metastasis

The immunosuppressive microenvironment in the brain poses a major limitation to successful therapy for brain metastases. Here we report that blockade of the ATP-to-adenosine-converting enzymes CD39 and CD73 and the adenosine receptor A2AR in combination with radiotherapy attenuates tumor progression in a breast-to-brain metastasis model by facilitating anti-cancer immunity. Immunophenotyping revealed loss of exhausted T cells and higher abundance of anti-cancer effector T cell populations. This effect was accompanied by a decrease of immunosuppressive lipid-laden macrophages and an expansion of CD14CD33high macrophages associated with antigen presentation. Analyses of human brain metastases samples supports a role of the ATP-adenosine signaling axis in modulating tumor inflammation and identified expression of CD39 and adenosine deaminase as predictive markers for patient survival and/or immune infiltration. Our findings demonstrate that the adenosine axis represents a druggable pathway to achieve local immunomodulation and treatment response, opening a new therapeutic avenue for brain metastases patients.

cancer biology↗

bioRxiv2022

AMP-kinase mediates adaptation of glioblastoma cells to conditions of the tumour microenvironment

AMP-activated protein kinase (AMPK) is a central cellular energy sensor that regulates metabolic activity. We hypothesised that in glioblastoma (GB), AMPK plays a pivotal role in balancing metabolism under conditions of the tumour microenvironment, which is characterised by fluctuating and often low nutrient and oxygen availability. Impairment of this network could thus interfere with tumour progression. AMPK activity was modulated genetically by CRISPR/Cas9-based double knockout (DKO) of the catalytic 1 and 2 subunits in human GB cells and effects were confirmed by pharmacological AMPK inhibition using BAY3827 and an inactive control compound in primary GB cell lines. We found that metabolic adaptation of GB cells under energy stress conditions (hypoxia, glucose deprivation) was dependent on AMPK and accordingly that, AMPK DKO cells were more vulnerable to glucose-deprivation or inhibition of glycolysis and sensitised to hypoxia-induced cell death. This effect was rescued by reexpression of the AMPK 2 subunit. Similar results were observed using the selective pharmacological AMPK inhibitor BAY3827. Mitochondrial biogenesis was regulated AMPK-dependently with a reduced mitochondrial mass and mitochondrial membrane potential in AMPK DKO GB cells. In vivo, AMPK DKO GB cells showed impaired tumour growth and tumour formation in CAM assays as well as in an orthotopic glioma mouse model. Our study highlights the importance of AMPK for GB cell adaptation towards energy depletion and emphasises the role of AMPK for tumour formation in vivo. Moreover, we identified mitochondria as central downstream effectors of AMPK signalling. The development of AMPK inhibitors could open opportunities for the treatment of hypoxic tumours.

cancer biology↗

bioRxiv2021

Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis

Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant non-malignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. We used an inhibitor of colony stimulating factor 1 receptor (CSF1R) to target TAMs at distinct stages of the metastatic cascade in preclinical breast-to-brain metastasis models and found that CSF1R inhibition leads to anti-tumor responses in prevention and intervention trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuro-inflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, combined blockade of CSF1R and STAT5 signaling led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.

cancer biology↗