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Characterization of intracellular signaling pathways modulated by the cellular prion protein on stemness maintenance in glioblastoma stem cells

Grant number: 19/14952-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2019
Effective date (End): August 31, 2021
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Marilene Hohmuth Lopes
Grantee:Bárbara Paranhos Coelho
Home 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

Among all tumors of the Central Nervous System (CNS), Glioblastoma Multiforme (GBM) is the most aggressive and resistant to standard treatments. Despite many studies, the mean survival of patients is only 15 months. 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. There are at least two signaling pathways that have great importance in the biology of stem cells, but are also relevant to GSCs: the Notch and Wnt/²- catenin. Both are involved on the regular biology of neural stem cells and are related to differentiation, proliferation and maintenance of the stemness, given that abnormal expression levels of proteins of these pathways are frequently observed in GSCs, and consequently in more aggressive types of GBM. Our group has demonstrated that the cellular prion protein (PrPC) and one of its most import ligands, (Heat shock organizing protein - HOP), are both overexpressed in GBM and that this increased expression is correlated to a higher proliferation rate and poor clinical prognosis. Recent data has shown that the PrPC-HOP complex promotes cell growth in GBM cell lines and the disruption of the interaction between PrPC and HOP using the HOP230-245 peptide inhibits GSCs self-renewal and GBM growth in vitro and in vivo. It was also demonstrated that silencing of PrPC decreased the expression of stem cell markers, self-renewal and tumorigenesis of GSCs. However, there is no knowledge about the downstream intracellular signaling pathways modulated by PrPC and its partners in GSC biology. So, the present project has as its main goal to study the signaling pathways mediated by PrPC in the maintenance of the stemness in glioblastoma stem cells through transcriptome analysis.