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

• Grant number: 19/14952-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): September 01, 2019
• Effective date (End): October 31, 2023
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Bárbara Paranhos Coelho
• 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

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.

Scientific publications

(7)

(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)

COELHO, BARBARA PARANHOS; PRADO, MARIANA BRANDAO; IGLESIA, REBECA; ESCOBAR, MARIA ISABEL M.; FERREIRA, FREDERICO M.; DOS SANTOS, TIAGO G.; NAKAYA, HELDER I.; LOPES, MARILENE H.. Knockout of cellular prion protein in glioblastoma affects the expression of Wnt signaling genes. Cancer Research, v. 82, n. 12, p. 2-pg., 2022-06-15. (19/14952-0)

ALVES, RODRIGO NUNES; IGLESIA, REBECA PIATNICZKA; PRADO, MARIANA BRANDAO; MELO ESCOBAR, MARIA ISABEL; BOCCACINO, JACQUELINE MARCIA; FERNANDES, CAMILA FELIX DE LIMA; COELHO, BARBARA PARANHOS; FORTES, AILINE CIBELE; LOPES, MARILENE HOHMUTH. A New Take on Prion Protein Dynamics in Cellular Trafficking. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 20, OCT 2020. (20/07450-5, 17/26158-0, 19/14952-0, 19/11097-1, 20/04687-4, 18/15557-4, 19/12710-9, 19/14741-9)

COELHO, BARBARA PARANHOS; DE LIMA FERNANDES, CAMILA FELIX; BOCCACINO, JACQUELINE MARCIA; DA SILVA SOUZA, MARIA CLARA; MELO-ESCOBAR, MARIA ISABEL; ALVES, RODRIGO NUNES; PRADO, MARIANA BRANDAO; IGLESIA, REBECA PIATNICZKA; CANGIANO, GIOVANNI; MAZZARO, GIULIA LA ROCCA; et al. Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma. FRONTIERS IN ONCOLOGY, v. 10, NOV 12 2020. (19/14552-1, 19/14952-0, 17/26158-0, 20/04687-4, 19/06971-4, 19/11097-1, 19/12710-9, 20/07450-5, 18/15557-4, 19/14741-9)

IGLESIA, REBECA PIATNICZKA; DE LIMA FERNANDES, CAMILA FELIX; COELHO, BARBARA PARANHOS; PRADO, MARIANA BRANDAO; MELO ESCOBAR, MARIA ISABEL; DONA RODRIGUES ALMEIDA, GUSTAVO HENRIQUE; LOPES, MARILENE HOHMUTH. Heat Shock Proteins in Glioblastoma Biology: Where Do We Stand?. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 22, NOV 2019. (18/15557-4, 17/26158-0, 18/19320-9, 19/14952-0, 17/20271-0, 19/12710-9, 19/11097-1)

COELHO, BARBARA PARANHOS; PRADO, MARIANA B.; FERREIRA, FREDERICO M.; DOS SANTOS, TIAGO G.; NAKAYA, HELDER I.; LOPES, MARILENE H.. The cellular prion protein is involved in the modulation of Wnt signaling in glioblastoma. Cancer Research, v. 83, n. 7, p. 2-pg., 2023-04-01. (19/14952-0)

FERNANDES, CAMILA FELIX DE LIMA; COELHO, BARBARA PARANHOS; SOUZA, MARIA CLARA DA SILVA; BOCCACINO, JACQUELINE MARCIA; SOARES, SAMUEL RIBEIRO; DE ARAUJO, JAO PEDRO ALVES; MELO-ESCOBAR, MARIA ISABEL; LOPES, MARILENE HOHMUTH. Extracellular vesicles throughout development: A potential roadmap for emerging glioblastoma therapies. SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, v. 133, p. 10-pg., 2023-01-15. (21/13070-3, 19/14952-0, 19/11097-1, 19/14741-9, 20/05443-1, 18/15557-4, 21/05287-2, 20/07450-5)

PRADO, MARIANA BRANDAO; MELO ESCOBAR, MARIA ISABEL; ALVES, RODRIGO NUNES; COELHO, BARBARA PARANHOS; FERNANDES, CAMILA FELIX DE LIMA; BOCCACINO, JACQUELINE MARCIA; IGLESIA, REBECA PIATNICZKA; LOPES, MARILENE HOHMUTH. Prion Protein at the Leading Edge: Its Role in Cell Motility. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 18, p. 18-pg., 2020-09-01. (19/14952-0, 19/11097-1, 19/14741-9, 17/26158-0, 19/12710-9, 18/15557-4, 20/07450-5, 20/04687-4)