Secreted EGFL7 governs blood-brain barrier integrity in malignant glioma

• Applicant: Professor Dr. Mirko H.H. Schmidt
• Subject Area: Anatomy and Physiology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547036223

Glioblastomas are among the most common malignant tumors of the central nervous system and are currently incurable. The life expectancy of patients upon initial diagnosis is currently only 15 to 18 months. In addition, disproportionately many young patients are affected by this disease, which results in a high loss of life and working years. Gliomas are characterized by an increased formation of new blood vessels, which display a quite heterogeneous formation of the blood-brain barrier. This barrier physiologically protects the brain from toxic substances, which limits the access of chemotherapeutic agents to the brain but unfortunately, also to the brain tumor itself. Mechanistically, glioblastomas influence blood vessels and the blood-brain barrier by releasing factors that create a tumor-promoting microenvironment. One of these factors is the epidermal growth factor-like protein 7 (EGFL7), which is secreted by endothelial cells and becomes incorporated into the extracellular matrix. The matrix of gliomas is stiffer compared to non-tumoral tissue, which can influence vascular integrity and permeability to chemotherapeutic agents. EGFL7 physiologically and pathologically stimulates the formation of new blood vessels in vivo and has a stabilizing effect on the blood-brain barrier. In addition, EGFL7-inhibiting antibodies have already been successfully used in glioma models to prolong survival. Newly generated mouse lines for the specific manipulation of EGFL7 in endothelial cells, mural cells and astrocytes in combination with state-of-the-art techniques make it now possible to better understand the influence of EGFL7 on the formation of new blood vessels and the blood-brain barrier in the central nervous system and in malignant brain tumors in order to target EGFL7 and comparable proteins for therapeutic interventions. In particular, we will focus on the composition, integrity and functionality of blood vessels. In this way, new target genes will be identified that will be manipulated to reduce the formation of new blood vessels within and close to brain tumors and to make malignant gliomas more accessible to chemotherapeutics by reversible opening of the blood-brain barrier. This will open up new therapeutic avenues for the treatment of patients suffering from malignant brain tumors.

• DFG Programme: Research Grants