The impact of cellular prion protein depletion in the modulation of signaling pathways and expression of prion-like proteins in glioblastoma stem cell biology

• Grant number: 18/19517-7
• Support type: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): January 25, 2019
• Effective date (End): September 24, 2019
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal researcher: Marilene Hohmuth Lopes
• Grantee: Mariana Brandão Prado
• Supervisor abroad: Martin Duennwald
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Western University , Canada
• Associated to the scholarship: 17/26158-0 - Prion protein as stem regulator in glioblastoma stem cells: its role in the formation and function of multiprotein signaling platforms, BP.DD

Abstract

The glioblastoma multiforme (GBM) is a tumor composed of glial cells. GBM is by far the most common and most malignant type of glioma, with high rates of recurrence and mortality. Studies have shown that GBM is maintained by stem cells like subpopulation denominated glioblastoma stem cells (GSCs). These cells self-renew, promote angiogenesis and invasion, and are also chemo and radio-resistant. Thus, GSCs have significant potential as a therapeutic target for the glioblastomas treatment. Recent studies have shown that cellular prion protein (PrPC) emerges as a key factor in the maintenance of GBM and GSCs. PrPC has an important role as a scaffold protein being capable to interact with several other membrane proteins and extracellular matrix, forming complexes able to regulate different functions in the tumor biology. In particular, PrPC co-localizes and is co-expressed with CD44 (a glycoprotein involved in cell-cell interactions) in treatment-resistant breast tumors. Recent data from our group suggest PrPC as a ligand of CD133 capable of modulating its intracellular traffic in GBM and, consequently, its function. Neurodegenerative disorders have poorly folded proteins, such as TDP-43 and SOD1, which propagate in a prion-like manner and are associated with Amyotrophic lateral sclerosis. Interestingly, similar to PrPC, these proteins are also related to the tumor biology. For example, TDP-43 is involved in the regulation of migration and survival in lung cancer cells. SOD1 is involved in the regulation of oxidative resistance and repair genes and in tumors promotes growth and resistance to apoptosis in lung cancer cells. Regarding the similarities between these proteins and PrPC capacity to recruit and interact with proteins involved in stemness, the principal aim of this study is: to evaluate the signaling pathways modulated by PrPC and its partners in the undifferentiated state of GSCs and the impact of prion-like proteins in this process. (AU)