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Tumor

THY1 confers proliferative advantages and therapy resistance in Glioblastoma.

Sunday, May 5, 2024
2:49 PM – 2:51 PM CT
Location:  S405a
Introduction: 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. Analyses of clinical databases revealed significant association of higher THY1 levels with worse overall survival.

Methods: Patient derived GBM organoid models, cell proliferation, immunoblot, immunflorescnece, and in vivo mouse model.

Results: Experimentally, we demonstrate that reducing levels of THY1 in both cell line and patient derived GBM organoid model (UM3506) retards the growth of cells, suggesting a critical role for THY1 in cell proliferation. THY1 knockout also led to increased sensitivity to Temozolomide/Radiation treatment in UM3506 organoid. Next, we overexpressed THY1 in U87 cells which do not exhibit detectable THY1 levels. Here, increased THY1 levels also led to resistance to Temozolomide/Radiation treatment in U87 grown as neurospheres. To explore if THY1 contributes to DNA damage repair, we measured the levels of gH2Ax staining in the U87 neurosphere model. Unlike GFP expressing U87 neurospheres, cells overexpressing Thy1 show remarkably low levels of gH2Ax staining indicative of minimal DNA damage after 4Gy radiation treatment. Together, these data suggest that THY1 is involved in the DNA damage repair process.
These THY1 overexpressing U87 neurospheres also show an neuronal precursor like (NPC-like) characteristics and suggest that the NPC-like state can be determined by THY1, known to be a neuronal marker in the normal brain. Finally, we show that dox inducible knockout of THY1 completely abrogates the ability of UM3506 organoid to establish tumors in mice. We are currently exploring this model to study the role of THY1 in therapy resistance.

Conclusion : 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.