TMIC-44. THY1 CONFERS PROLIFERATIVE ADVANTAGES AND THERAPY RESISTANCE WITHIN LOCALIZED NICHES OF GLIOMA

Abstract

Abstract Resistance to therapy is a hallmark of Glioblastoma (GBM), making it a deadly disease. Earlier, using a longitudinal mouse model, we reported that the immunoglobulin-like cell surface receptor THY1, was significantly upregulated in recurrent GBM tumors. Here, we used single cell and spatial transcriptomics data to track THY1 expression through treatment resistance. Single cell analysis of primary and recurrent GBM shows that THY1 expression is significantly associated with multiple tumor cell states, namely, the NPC-like (Neuronal precursor-like), OPC-like (oligodendrocyte precursor-like) and MES-like (mesenchymal-like) cellular states. Further, spatial analysis of primary GBM shows that tumor cells resident in highly vascularized regions and at invasive edges express significantly high levels of THY1. Specifically, high THY1 levels at the invasive edge is associated with NPC-like state, known to migrate through white matter tracts in vascular regions. In contrast, THY1 expression is high in MES-like cells within recurrent GBM tumor cells. Single cell analysis of a matched primary and recurrent tissue shows a remarkable increase in THY1 expression upon recurrence coincident with a switch to predominantly MES-like state. Using protein markers that define different cellular states we performed immunofluorescence analyses to track the expression of THY1 across both primary and recurrent tumors. We show evidence of high THY1 protein expression associated with NPC-like cells in different niches within primary tumors. In recurrent GBM tissues, THY1 protein expression is significantly higher and present along the palisading regions surrounding necrosis. Finally, we show that dox inducible knockout of THY1 completely abrogates the ability of a patient derived organoid to establish tumors in mice. We are currently exploring this model to study the role of THY1 in therapy resistance. Together, these data suggest that THY1 is critical for tumor growth and upon therapeutic stress can contribute towards shift in tumor cell identity to generate therapy-resistant clonal populations.