Glioblastoma (GBM) is the most frequent and most lethal type of brain cancer in adults, with poor survival rates of 15-20 months with therapy. The crosstalk between GBM and host cells in the tumour microenvironment (TME) promotes tumour progression, heterogeneity, and therapy resistance that together exacerbates poor survival. We have previously shown that host astrocytes can positively or negatively affect brain tumour invasion into the surrounding parenchyma, depending on the status of astroglial reactivity.

Here, we investigate cell-cell interactions between GBM and host astrocytes in patient-derived orthotopic xenografts and syngeneic in vivo models. We find that GBM-astrocyte crosstalk promotes the expression of the cell-plasticity associated transcription factor, ZEB1, both in GBM and in host astrocytes. We have previously demonstrated that ZEB1 is a key regulator of GBM cancer stem cells and mediates tumour invasion and therapy resistance. ZEB1 is expressed in neurogenic stem/progenitor cells in the developing and adult brain, where it promotes self-renewal. The functions of ZEB1 in astrocytes remain unclear.

Using a conditional-inducible transgenic mouse model for deletion of Zeb1 in murine astrocytes we find that loss of host astrocyte plasticity restricts tumour invasion and increases animal survival remarkably. Single cell transcriptional profiling of tumour-bearing control and Zeb1-deleted mice identifies key alterations of astrocyte states as well as immune cell activation which contribute to GBM tumour progression. Additionally, we identify ligand-receptor candidates that mediate crosstalk between astrocytes, GBM and immune cells and which may constitute therapeutic targets for reprogramming the host TME to reduce GBM progression.

Our findings demonstrate that host astrocytes in the TME are powerful regulators of GBM growth and that reprogramming host astrocytes can block brain tumour progression.