gms | German Medical Science

Objective: Glioblastoma (GBM) depend on support by their local environment. Vascular cells as well as tumour-associated myeloid cells (TAM) constitute the major components of the GBM-parenchyma. TAM, which consist of microglia and peripheral macrophages, accelerate GBM cell-invasion and the rich vascular network of GBM has important tumour-trophic functions. In this study, we identified a previously unacknowledged population of a local myeloid progenitor cell that transiently appeared during glioblastoma growth.

Methods: Using a glioma mouse model for lineage-tracing of tumor-parenchymal cells (nestin-creER2, R26-tdTomato; abbreviated as nestin-reporter mice), we observed (by single cell transcriptomics and immunofluorescence analysis) a subset of tumor-associated avascular cells over a time-course. In different transgenic mouse strains and in bone-marrow chimeric models we investigated the point-of-origin as well as the lineage-identity of these traced cells. These cells were further characterized by immunofluorescence in mouse models and patient samples of GBM. In a functional experiment, we induced a knockout of the transcription factor SOX2 in the traced tumor-associated cells and effects on tumor-progression were compared to SOX2 wild-type controls.

Results: The population of tumor-associated lineage-traced cells in the nestin-reporter model had remarkable similarity with microglia. However, they were distinct from TAM as they have no microglial origin and do not derive from the bone marrow. Strikingly, these traced cells derived from a local progenitor cell that is dormant in brain homeostasis. Induction of orthotopic glioma in nestin-reporter activated this SOX2-dependent progenitor cell population (as assessed in n>15). Abrogation of this progenitor cell-population by conditional Sox2-knockout ablated the entire subset of these traced cells with a myeloid expression profile (TAMEP; n= 9 vs. 8 for control vs. ablated). Histopathological inspection showed that the small subset of TAMEP has large impact on disease-progression by reducing glioblastoma-vascularizationby over 40%(with statistical significance of P<0,005 by T-test)and -size by more than 60% (withP<0,05 by T-test).

Conclusion: Our data suggest that dormant progenitors generate TAMEP (which are cells expressing myeloid markers but lacking a myeloid origin) that have profound neurooncological impact and point towards a new and promising therapeutic target in order to support anti-angiogenic regimen in GBM.