MB-11: RESTRICTING GROWTH AND SPREADING OF MEDULLOBLASTOMA BY BLOCKING KINASE-DEPENDENT BRAIN INFILTRATION

Metastatic dissemination of medulloblastoma (MB) is causative for mortality and therapy-related high morbidity rates in cured patients. How metastasis proceeds in MB is poorly understood but in vivo studies and clinical data suggest that tumour cells infiltrate locally into the surrounding cerebellar tissue during early stages. Thus, we explore and pre-clinically validate approaches that specifically target infiltration and growth of MB cells in the cerebellar tissue. We have developed a sensitive platform for diagnostic and prognostic testing of factors involved in control of motility and invasiveness in laboratory lines or patient-derived xenograft and primary MB tumour cells. We determined the sensitivity of the tumour cells to growth factors or anti-metastatic compounds, and identified HGF, EGF and bFGF as molecular subgroup-independent, strong promoters of cell dissemination in vitro. We show that the pro-migratory signalling emanating from growth factor stimulation is mediated by MAP4K4, a druggable Ser/Thr kinase. To study brain infiltration, we established a novel, ex vivo organotypic brain slice/tumour-spheroid co-culture system. We found that MB tumour cells disseminate and grow into new tumour clusters by infiltrating intact cerebellar tissue. We demonstrated that organotypic growth and dissemination of MB could be visualized and quantified at high temporal and spatial resolution using confocal microscopy. Thus, this system represents an attractive ex vivo model to address the mechanisms underlying pathogenic brain infiltration. Using this approach, we pre-clinically validate the therapeutic potential of specifically blocking growth factor signalling, and explore MAP4K4 inhibition as a potential anti-dissemination strategy in a physiologically relevant tissue environment.