Effect of intervention astrocyte phenotype on glioblastoma

The high invasiveness of gliomas is the main reason for the difficulty in treating them. At the invasion front, glioma cells mainly contact and activate astrocytes, but the characteristics and function of these subpopulations are still unknown. A1 and A2-astrocytes have been identified in central nervous system disorders. However, their role in glioblastoma has not been fully explored. In this study, we revealed the function of A1 and A2-like astrocytes in the glioma microenvironment and demonstrated that the transition between these subpopulations is regulated by the TGF-beta signaling pathway, and inhibiting this pathway can promote the transformation of A2-like to A1-like phenotype, thereby suppressing the malignant progression of gliomas and improving the efficacy of chemotherapy. First, we used immunofluorescence staining to confirm the absolute dominance of A2-like astrocytes in G422TN, GL261 glioma models and clinical glioma samples, and used bioinformatics analysis to confirm the association of A2-like astrocytes with malignancy and poor prognosis in gliomas. Next, we injected AAV-DIO-DTA virus into hGFAP-CreERT2 mice to ablate A2-like astrocytes and observed inhibited tumor growth and prolonged survival of the tumor-bearing mice. Transcriptomic and histological analysis showed that the ablation of A2-like astrocytes primarily inhibited glioma cell proliferation. We then found that TGF-beta signaling plays a key role in the transformation of A1/A2 subpopulation. Inhibition of TGF-beta signaling in astrocytes by hGFAP-CreERT2; Tgfbr2flox/flox transgenic mice reversed the absolute dominance of A2-like astrocytes and disrupted the malignant progression of gliomas. Transcriptomic and histological analyses showed that inhibition of TGF-beta signaling in astrocytes inhibited the proliferation and invasion of glioma cells. Finally, we found that inhibition of A2-like astrocytes synergized with chemotherapy drugs to enhance the therapeutic efficacy and significantly prolong the survival of tumor-bearing mice.