Research > Focus A > Work Packages A07

Mapping and targeting neuron-tumor networks to tackle therapy resistance in glioblastoma

Summary

The contribution of neuron-glioma synapses to resistance against chemo- and radiotherapy will be studied using state-of-the-art imaging technologies that allow for high-throughput screening and analyses of tumor-neuron networks. Molecular determinants of neuron-tumor synapses are analysed through multi-omics in both preclinical models and patient material. We aim to identify if disrupting neuron-tumor synapses can be synergistically used with standard-of-care approaches to overcome therapy resistance.

Task 1

Development and validation of methods to quantify neuron glioma synapses as a cellular mechanism and a biomarker for therapy resistance in gliomas

Steps / Workflow

Establish high-through-put microscopy methods to quantify neuron glioma synapses in large tissue volumes across cell states
Compare neuron glioma synapses patient derived xenograft models (+/- radiochemotherapy, +/- AMPAR inhibition) across tumor cell states
Validate findings based on paired primary and recurrent human glioma tissue samples

Task 2

Functional and molecular characterization of neuron glioma synapses in therapeutic resistance

Steps / Workflow

Investigate functional communication of neuron glioma synapses with patch clamp electrophysiology and calcium imaging under therapy
Use scRNAseq , spatial transcriptomics and proteomics to investigate the molecular composition of neuron tumor networks under therapy

Task 3

Pharmacological perturbation of neuron glioma synapses to study effects on tumor resistance.

Steps / Workflow

Pharmacological in vitro screen in neuron/astrocyte co-cultures in combination with standard-of-care therapy
In vivo screening of 3 compounds from the in vitro screening by 2-photon imaging, MRI and whole brain lightsheet microscopy
Determine synergistic effects with combinations of anti neuron glioma synaptic compounds and standard of care therapy