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Prion protein and its partners: emerging targets for glioblastoma stem cell based-therapy

Grant number: 18/15557-4
Support type:Research Grants - Young Investigators Grants- Phase 2
Duration: May 01, 2019 - April 30, 2024
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Marilene Hohmuth Lopes
Grantee:Marilene Hohmuth Lopes
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Bruno Costa da Silva ; Frank Furnari ; Frederico Moraes Ferreira ; Marco Antonio Maximo Prado ; Tiago Góss dos Santos
Associated research grant:11/13906-2 - Contribution of the co-chaperone STI1 in mouse development: embryonic stem cell as approach, AP.JP

Abstract

Glioblastoma (GBM), the most aggressive and frequent form of brain malignant tumors in adults, contains a subpopulation of tumor cells called GBM stem cells (GSCs), essential for tumor maintenance, invasion and resistance to therapy. Functionally relevant GSCs plasma membrane markers present potential as a therapeutic target for the treatment of this aggressive disease. Our group has shown that the GPI-anchored membrane glycoprotein, prion protein (PrPC) is enriched in GSCs and is co-expressed with conventional GSC markers. The loss-of-function of PrPC in GSC results in the inhibition of self-renewal, proliferation and capacity for tumor formation. We have proposed that PrPC acts as a scaffold protein on the cell surface, recruiting and organizing molecules on signaling platforms with different biological consequences. In light of these findings, this study aims to investigate the role of PrPC as a key molecule in GSC biology, modulating pathway signaling platforms associated with stemness and differentiation processes and as a target for GBM therapy. We proposed to address this question by using four different paradigms: 1) in vitro assays using patient-derived GSCs cultures to assess the function of PrPC and partners in the biology of these cells; 2) Transcriptome profiling using Exon Microarray and RNA-seq to define the PrPC and partners expression pattern, to quantify PrPC targets and downstream signaling pathways up/downregulated according to PrPC expression; 3) in vivo assays using GSCs to target PrPC, its partners and/or intracellular signaling-related proteins in combination with temozolomide; 4) in vitro assays to test the effect of extracellular vesicles into directed specification of GSCs toward the neuronal lineage as alternative for anti-GBM therapy. Thus, this proposal will employ the scaffold concept for PrPC as an alternative for the development of new strategies for the treatment of GBM and to demonstrate that PrPC might act as a key regulator interconnecting functions related to GSCs stemness maintenance. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE LIMA FERNANDES, CAMILA FELIX; IGLESIA, REBECA PIATNICZKA; MELO-ESCOBAR, MARIA ISABEL; PRADO, MARIANA BRANDAO; LOPES, MARILENE HOHMUTH. Chaperones and Beyond as Key Players in Pluripotency Maintenance. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 7, AUG 2 2019. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.