表征胶质母细胞瘤与少突胶质前体细胞之间的竞争性相互作用

Resection of glioblastoma (GBM) often only includes the contrast-enhancing (CE) solid portion of the tumor and radiation therapy also targets this region. These therapies leave behind infiltrating tumor cells that lay beyond the CE border in the non-enhancing region (NE) with the capacity to propagate the tumor following therapy. Non-transformed cell types in the brain have been shown to promote GBM progression via a variety of mechanisms. We performed single nucleus RNA-sequencing (snRNA-seq) on 17 biopsies from the NE and CE regions of seven different primary IDH WT glioblastoma tumors during maximal resection surgery. While some oligodendrocyte progenitor cells (OPCs) are present in the NE region, they are almost absent in the CE region, a finding corroborated by our prior study of recurrent tumors. OPCs, the most common cycling cells in the brain, share many genes with GBM and the interaction between the two cell types has yet to be described on a single cell level. Prior work has demonstrated that in the developing and adult brain young, more fit OPCs can outcompete older OPCs leading us to hypothesize that brain tumor cells can compete with non-transformed OPCs. To explore possible interactions between GBM and OPCs we utilized predictive cell-cell interaction software, finding that OPCs express transcripts that are predicted to respond to GBM signals to induce proliferation, migration and differentiation. Compared to snRNA-seq of healthy OPCs, the OPCs from our biopsies were more likely to be proliferative, migratory, and differentiated. To assess possible enrichment of pathways associated with a more competitive state, we performed differential expression between OPCs contained in our biopsies and GBM cells. This revealed a significant enrichment of the YAP1 pathway which is associated with a more competitive state. GBM cells were predicted to be activated by OPCs to proliferate, migrate and have increase synaptic activity. To investigate how soluble factors secreted by OPCs and GBM cells influence each other by culturing each cell population in conditioned media (CM) derived from the opposite cell type. OPCs treated with GBM CM have shown increased proliferation and GBM cells treated with OPC CM have shown decreased proliferation, possibly due to younger nature of OPCs that were differentiated from iPSCs. Our findings support the hypothesis that there are complex and possibly competitive interactions between OPCs and GBM cells, extending the concept of “cancer neuroscience”. Further studies are ongoing to establish the nature and mechanisms of these interactions.