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Modulation of PrPC and CD44 expression in Glioblastoma stem-cells and its role on intracellular trafficking and vesicle biogenesis

Grant number: 22/08198-3
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2022
Effective date (End): April 30, 2024
Field of knowledge:Biological Sciences - Biology
Principal researcher:Marilene Hohmuth Lopes
Grantee:Rodrigo Nunes Alves
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

Glioblastoma Multiforme (GBM) is a highly aggressive glial tumor, with a high recurrence and death rates. Recent studies indicate that the GBM is maintained by a subpopulation of cellswith stem-cell characteristics, denominated Glioblastoma Stem Cells (GSCs). Recently ourgroup has identified the Cellular Prion Protein as having an important role in the modulationof the GSCs undifferentiated state. Our group has described the role of the Protein Prion Celular 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. A potential ligand of PrPC is CD44, a well known glycoprotein involved in cellular adhesion and migration processes of GSCs, possibly interacting with PrPCin membrane microdomains denominated lipid rafts. Studies have shown the capacity of neural stem cells to reduce stem-like phenotypes in GSCs, induce its differentiation and suppress tumor growth in vivo. On the other hand, GSCs can be the starting point of a brain tumor, being a population that is highly related to the tumor microenvironment while also having a tumor-specific tropism. Extracellular vesicles had been recognized as intracellular messengers implicated in the transfer of distinct molecules, including miRNA, to modify the phenotype of the recipient cell. Remarkably, PrPC plays a role in exosomes modulating their secretion level through a caveolin dependent complex that drives autophagosome formation. Furthermore, CD44 is also related to both the endocytic and the exocytic pathways, being able to modulate intracellular trafficking as well as EVs secretion by being a main component of exosomes in different types of tumor. Our theory is that PrPC and its partner CD44 may be participating in the stem-cells phenotype regulation through EV-communication with the tumor microenvironment and with that in mind, the aim of this project is to study the modulation of PrPC and CD44 expression in glioblastoma stem-cells and its role on intracellular trafficking and vesicle biogenesis. (AU)

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