Multidimensional analysis and therapeutic targeting of microglia fostering brain tumor relapse

Microglia mediates innate immunity in the CNS and is of central importance for the development of new clinical concepts in neuroinflammation, neurodegeneration and neurooncology. Brain biopsies, e.g. from surgical resections of aggressive brain tumors (glioblastomas; GBM) were instrumental to gain insight into the pathological role of microglia and monocyte-derived macrophages in humans. However, this largely provided data on the biology of the primary tumor mass, which is surgically removed as a front-line therapy for GBM. GBM almost invariably relapse and thereby cause the enormous mortality rate of these tumors.
It is now urgently required to investigate the interplay of infiltrative GBM cells (left behind after surgery) with parenchymal microglia and their contribution to GBM recurrence. Infiltrative GBM cells interact with microglia and can thereby acquire signals supporting GBM cell viability, immune-evasion and chemoresistance, which ultimately lead to tumor-regrowth and death.

We have established a robust and flexible mouse model for relapsing GBM that recapitulates the invasive pattern of the recurrent tumor and can be combined with standard neurooncological therapy. Together with our broad panel of genetically engineered mouse models for brain tumors, macrophages or microglia this provides a solid basis to investigate the interplay of microglia with scattered GBM cells in the brain parenchyma.
Furthermore, we have already identified human microglia derived, relapse promoting signaling cues, which constitute direct therapeutic targets and co-explain the sex-related bias in this disease.
For our preclinical assays we have developed appropriate, humanized in situ models (using human induced pluripotent stem cell derived microglia, IPSC, in brain slice preparations) for GBM.
Finally, we have obtained innovative and clinically applicable therapeutics with high CNS tropism that are suited to block microglia promoted GBM recurrence.
We will address a critical time-window after neurosurgery and before radio-chemotherapy that provides a particular opportunity for targeted therapies. Furthermore, we will interfere with microglia promoted chemoresistance during standard therapy.
In addition to our identified molecular targets we will use genetic and cell biological techniques in IPSC and transgenic mice to spatiotemporally characterize the clonal expansion of disease promoting microglia.

Our project will identify distinct microglia subsets with pro-neoplastic properties and will provide new preclinical concepts to prevent microglia supported GBM relapse.

Our current data show that release of human-specific signaling molecules from microglial cells can provide a strong growth- / survival-signals for dispersed GBM cells after surgery and that drug repurposing (of clinically approved substances) offers a way to block the tumor supporting effect of microglia. In a series of experiments using (single cell) transcriptomics, proteomics, flow cytometry, pharmacology, iPS-derived human microglia in brain slice cultures and humanized mouse models for GBM we will develop translational concepts blocking microglia initiated GBM relapse.