TMZ resistance in glioblastoma stem cells expressing distinct PrPc levels in normoxia and hypoxia culture conditions

• Grant number: 20/10671-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): November 01, 2020
• Effective date (End): October 31, 2021
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Giovanni Cangiano
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/15557-4 - Prion protein and its partners: emerging targets for glioblastoma stem cell based-therapy, AP.JP2

Abstract

The Glioblastoma Multiforme (GBM) is a highly aggressive glial tumor, with a high recurrence and death rates. Within the tumor mass, there are groups of cells that have features of stem/progenitor cells, named glioblastoma stem cells (GSCs) and possess large potential for proliferation and differentiation. GSCs have an important role in growth, maintenance and recurrence of cancer, even after conventional treatment. Our group has described the role of the Protein Prion Celular (PrPc) in the biology of the GSC, being involved in the modulation of proliferation and self-renewal of those cells. The PrPc is a GPI-anchored protein, capable of acting as a scaffold protein, forming complexes with multiple proteins, such as stemness markers. Also, PrPc loss-of-function inhibits GSCs self-renewal, proliferation and tumor initiating capabilities. Our preliminary results show that PrPc-depleted glioblastoma cell lines present sensitivity to TMZ and downregulation of MGMT. TMZ resistance in GBM is frequent in hypoxic niches and is related to MGMT expression and methylation. A better understanding of hypoxic niches may be critical to improve current anticancer strategies and targeting PrPc present potential to modulate important molecules expressed in these undifferentiated and chemo resistant cells of the niche. Thus, the main goal of this study is to evaluate the sensitivity of GSC expressing different PrPc levels to TMZ.