P12.02.A UNRAVELLING THE CROSSTALK BETWEEN GLIOMA AND OLIGODENDROCYTES IN THE HUMAN BRAIN

Abstract BACKGROUND Gliomas are primary brain tumors that carry glial characteristics and that maintain an intricate relationship with surrounding brain tissue facilitating both tumor cell proliferation and migration. The infiltrative nature of adult-type diffuse gliomas makes tumor recurrence after treatment inevitable, necessitating novel insights into the interaction of glioma cells with their surroundings to facilitate the development of more effective anti-tumor treatments. Tumor cells migrate over white matter tracts and are thought to cause a loss of white matter integrity. Accordingly, myelin protein has been identified in glioma patients’ cerebral spinal fluid indicating myelin breakdown. Myelin is produced by oligodendrocytes and the oligodendrocyte lineage comprises oligodendrocyte precursor cells (OPCs), pre-myelinating oligodendrocytes (pre-OLs) and mature myelinating oligodendrocytes (OLs) and has remarkable regenerative capacities. It is therefore likely that cells in the oligodendrocyte lineage play a key role in the response of the brain to glioma. Yet, it remains unknown how the tumor microenvironment of various glioma subtypes affects cells in the oligodendrocyte lineage. METHODS To investigate this, we have employed resected brain tissue from 12 glioma patients to perform histological assessment of the oligodendroglial lineage in tumoral, peritumoral and normal-appearing brain tissue. Next to this, we also performed cultures of primary human OPCs extracted from glioma peritumoral tissue from 9 glioma patients to investigate whether the glioma microenvironment affects the innate proliferation, differentiation and myelination capacity of OPCs. RESULTS Preliminary results indicate possibly higher numbers of oligodendroglial lineage cells (OPCs, preOLs and OLs combined) in the peritumoral tissue of IDH-mutant astrocytomas as compared to IDH-wildtype glioblastomas, while the population of preOLs and myelinating OLs was increased in peritumoral tissue of IDH-wildtype glioblastomas. In line with this, in culture, astrocytoma-derived OPCs exhibit a higher proliferative capacity, while a larger percentage of glioblastoma-derived OPCs reach a mature myelinating stage. CONCLUSION These findings suggest that IDH-mutant astrocytomas and IDH-wildtype glioblastomas may differentially affect the oligodendroglial population. To understand the molecular mechanisms underlying these differences, we are currently culturing OPCs with conditioned medium from patient-derived glioma cells. As such, our project will contribute to an enhanced understanding of the interactions between glioma subtypes and oligodendrocytes and may eventually help uncover novel treatment strategies to halt tumor recurrence. Support: Dutch Research Council (NWO Vidi grant 198.015), Amsterdam University Fund (AUF 5191), Amsterdam UMC Starter Grant (24.04.121).