Comparing Tumor Cell Invasion and Myeloid Cell Composition in Compatible Primary and Relapsing Glioblastoma

SIMPLE SUMMARY: We established a new minimally invasive mouse model for GBM relapse. For this, we utilized orthotopical implantation of HSVTK-transduced GBM cells and pharmacological treatment with GCV. In addition, we implanted patient-derived GBM cells of primary or recurrent tumors. We found that recurrent GBM were more aggressively invasive than primary GBM. Moreover, the recurring tumors had a higher ratio of monocyte-derived macrophages among the entire population of tumor associated myeloid cells. This shift in the composition of tumor-associated immune cells appeared to be independent from cell-death signaling or surgical intervention. This model provides the means to investigate the entire process of tumor relapse and test standard as well as experimental therapeutic strategies for relapsing GBM under defined conditions. ABSTRACT: Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be combined with conventional therapeutic approaches. Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism. This is followed by GBM re-growth over a predictable timeframe. Pharmacological de-bulking followed by tumor relapse was accomplished with an orthotopic mouse glioma model. Relapsing experimental tumors recapitulated pathological features often observed in recurrent human GBM, like increased invasiveness or altered immune cell composition. Orthotopic implantation of GBM cells originating from biopsies of one patient at initial or follow-up treatment reproduced these findings. Interestingly, relapsing GBM of both models contained a much higher ratio of monocyte-derived macrophages (MDM) versus microglia than primary GBM. This was not altered when combining pharmacological de-bulking with invasive surgery. We interpret that factors released from viable primary GBM cells preferentially attract microglia whereas relapsing tumors preponderantly release chemoattractants for MDM. All in all, this relapse model has the capacity to provide novel insights into clinically highly relevant aspects of GBM treatment.