PhD defence R.M. (Rute) dos Santos Moreira Pedrosa

This project was aimed at the identification of molecular pathways leading to the formation of brain metastases of patients with common cancers. By comparisons of gene expression patterns between women with breast cancer with and without brain metastases, we identified a prominent role of the T cell response in the formation of cerebral metastases of breast cancer (BCBM). In an in vitro model of the blood-brain barrier (BBB), we showed that co-culturing T lymphocytes with breast cancer cells results in accelerated passage. To a lesser extent, this appeared also to be true for other cancers. T lymphocyte contact causes the overexpression of Guanylate binding protein 1 (GBP1) and silencing of GBP1 strongly reduces the capacity of the breast cancer cells to pass the BBB. The strongest stimulatory effect on passage through the BBB appeared to come from the CD8+ T lymphocytic fraction. By using IFN-γ inhibitory antibodies, or alternatively, blocking the IFN-γ receptor 1 (IFNGR1) in breast cancer cells, we reached significant impairment of the passage of breast cancer cells through the BBB. Comparison of the proteome changes, induced by T lymphocyte contact of all tested cancer cell types, led to the identification of one commonly overexpressed protein, Coronin 1A (CORO1A). Similar to GBP1, CORO1A is a type I Coronin known to bind F-actin and localized to actin-rich cellular structures, playing a wide variety of actin-based motility processes. The facilitating effect on passing through the BBB of Coronin 1A was validated in functional assays.

The public defence will take place at the Senate Hall, 1st floor Erasmus Building, location campus Woudestein. The ceremony will begin exactly at 10.30 AM. In light of the solemn nature of the ceremony, we recommend that you do not take children under the age of 6 to the first part of the ceremony.