TMIC-50. HYPERACTIVATING THE HIPPO PATHWAY EFFECTOR TAZ DISTORTS THE TUMOR MICROENVIRONMENT, PROMOTES TUMOR-ENTRAINED NEUTROPHIL INFILTRATION, AND PHENOCOPIES MESENCHYMAL-GLIOBLASTOMA

Abstract

Glioblastoma (GBM), the deadliest and most common primary CNS malignancy in adults, is highly heterogeneous with variable prognoses and treatment responses. The molecular underpinnings for such variability remain largely unclear. Mesenchymal (MES)-GBMs, associated with poorest prognosis and highest treatment resistance, exhibit hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ), the major effector of the Hippo tumor suppressive pathway. Additionally, the tumor microenvironment (TME) of MES-GBMs appears to be altered, containing more infiltrative tumor-associated macrophages and microglia than GBMs of other subtypes. Moreover, the Hippo pathway has recently been shown to be involved in suppressing tumor immunogenicity. Yet, it remains elusive whether TAZ dysregulation distorts the TME to contribute to MES transition and tumor progression of MES-GBMs. We suspected that such TME distortion facilitates tumor immune evasion, MES transition, and tumor progression, therefore worsening prognoses and treatment responses. To test this, we generated three GBM cell lines expressing various forms of TAZ: 1) GBM^4SA expressing constitutively-active TAZ 2) GBM^4SA-S51A expressing TAZ incapable of binding to its downstream effector, TEAD, and 3) GBM^vector, vector control. We found mice orthotopically implanted with GBM^4SA phenocopied MES-GBM patients and exhibited significantly shorter survival. Histopathology revealed that GBM^4SA highly resembles human GBMs, with high cellular and nuclear anaplasia, microvascular proliferation, and pseudopalisading necrosis. Moreover, TME analyses from these GBMs suggested that GBM^4SA contains significantly more infiltrative myeloid cells than GBM^4SA-S51A or GBM^vector, suggesting that hyperactivity of TAZ leads to an altered TME. While most infiltrative myeloid cells in the GBM^vector or GBM^4SA-S51A TME were of monocyte lineage, those in the GBM^4SA TME were predominantly granulocytic, likely representing neutrophils. We will further delineate the roles of each myeloid cell type in the MES-GBM TME in driving tumor progression and treatment resistance, and we hope to draw implications for future GBM clinical management and novel TME-targeted anti-GBM therapies.