INTRINSIC OR INDUCED AGGRESSIVENESS-LINKED REGULATION OF VEGFC IN MEDULLOBLASTOMA CELL LINES

International audienceMedulloblastoma (MDB) is the most common pediatric malignant brain tumor. MDB is a very heterogeneous disease that consists of four subgroups, each of them with different molecular profiles, metastasis status and clinical outcomes. Treatment of MDB includes surgery, radiotherapy and chemotherapy. It cures 70% of the pa'ents nevertheless with many side effects. Relapse is always fatal. Understanding the mechanisms of this relapse might lead to the development of new targeted treatments. VEGFC and lympha'c markers are the main actors of the metasta'c process in many tumors. We thus meant to determine their role and regula'on in MDB-derived cells. We demonstrated that low-aggressiveness MDB-derived cells, DAOY, expressed high basal amounts of lympha'c marker mRNAs and proteins (VEGFC, PROX1, NRP2). Conversely, highly aggressive cells, HD-MB03, presented low amounts of these markers. X-ray irradia'on treatment of the cells induced a rise in VEGFC, at the mRNA and protein levels. We thus ques'oned the regula'on of lympha'c markers in MDB cells. We observed that in the highly aggressive HD-MB03 cells, VEGFC mRNA amount relies upon a very ac've NF-κB-dependent promoter, but that the mRNA gets intensely degraded, hence the low level of VEGFC mRNA in these cells. Conversely, DAOY cells present low ac'vity of VEGFC promoter and high stability of the synthesized mRNA. The promoter ac'vity is independent from NF-κB. Moreover, while VEGFC is secreted in DAOY cells, it is retained inside the cytoplasm of HD-MB03 cells. Since VEGFC is so precisely regulated in MDB cells, it may play an important part in MDB aggressiveness. HSP 90 VEGFC Claudin DAOY Clone 1 HD-MB03 DAPI DAPI DAPI VEGFC VEGFC VEGFC Merge Merge Merge Intrinsic characterisOcs of MB cell lines DAOY (SHH): High expression of lymphaOc markers and VEGFC > Low proliferaOon and high migraOon rates HDMB-03 (Grp3): High expression of lymphaOc markers and VEGFC > High proliferaOon and low migraOon rates VEGFC has a impact on the proliferaOon of HD-MB03 cells. VEGFC DAOY VEGFC promoter VEGFC VEGFC mRNA HD-MB0