Abstract 3909: THY1 regulates therapy resistance in glioblastoma recurrence

Abstract

Abstract Glioblastoma (GBM), is the most common primary brain tumor. It is a lethal disease with a median survival of 15 months characterized by treatment resistance, aggressive brain invasion, and inevitable recurrence. Less than 10 percent of patients survive beyond 5 years. Here, we developed an intracranial longitudinal in vivo recurrence model using HF2303, a patient derived explant, to produce paired specimens (pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR) treatment. Mouse brain tissues from the two groups were compared to identify genes and pathways driving treatment resistance. This analysis showed an elevated THY1 expression in recurrent HF2303 tumors compared to naïve tumors. Increased Thy1 expression was also associated with a more mesenchymal phenotype. THY1 expressing cells from naïve HF2303 were also resistant to TMZ/IR treatment in an intracranial model. In U87 neurospheres, overexpression of THY1 increased resistance to TMZ/IR. Interestingly, stable knockdown of Thy1 in GBM cells and human derived GBM organoids (GBOs) expressing high THY1 levels led to reduced cell proliferation. Yet, an inducible knockout of THY1 using CRISPR/Cas9 in human GBOs showed increased sensitivity to TMZ/IR. This suggests a clear link between THY1 expression and TMZ/IR resistance.Single cell RNA sequencing of over 25 primary GBM and 4 recurrent tumors (spanning over 120,000 cells) shows that cells expressing high levels of THY1 are associated with two distinct populations; neuronal precursor-like (NPC-like) and mesenchymal-like (MES-like). Furthermore spatial transcriptomics from 3 primary GBMs suggests that high THY1 expressing cells are colocalized with macrophages within the perivascular niche contributing to the mesenchymal phenotype. We will present these studies and our more recent work analyzing spatial recurrent GBM samples. Particularly, we will address how THY1 expression in these spatially distinct NPC-like and MES-like differ and how each of these states may contribute towards TMZ/IR resistance. Citation Format: Sunita Shankar, Visweswaran Ravikumar, Hanxiao Wang, Sunjong Ji, Zainab Hasan, Ziad Fehmi, Yacoub Haydin, Daniel R. Wahl, Arvind Rao, Alnawaz Rehemtulla, Wajd Al-Holou. THY1 regulates therapy resistance in glioblastoma recurrence. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3909.