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

• Grant number: 18/15557-4
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: May 01, 2019
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Marilene Hohmuth Lopes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated 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
• Associated scholarship(s): 24/15190-4 - Effects of miRNAs secreted by extracellular vesicles on dopaminergic neuron specification in cellular (2D/3D) models of Parkinson's disease, BP.DR; 24/21638-8 - Study of the Role of STIP1 in the Regulation of Proteostasis and Pluripotency in Human iPSCs, BP.IC; 24/07492-0 - Modulation of STI1 expression: Effects on the pluripotency status mediated by the Wnt signaling pathway, BP.DD; + associated scholarships 23/12507-4 - The Impact of Prion Protein on Gliomagenesis: Unraveling Molecular Pathways in Patient-Derived Tumor Stem Cells, BP.DD; 23/12717-9 - Human PRNP gene transcription factors characterization as possible therapeutic targets: anti-tumoral strategies against glioblastoma., BP.IC; 22/14445-3 - Impacts of STI1 modulation on Wnt signaling and pluripotency status, BP.MS; 23/04293-4 - Impact of cellular prion protein in temozolomide resistance of glioblastoma stem cells mediated by HIF1±., BP.PD; 22/03802-0 - Extracellular vesicles derived from neural precursors as modulators of the tumor microenvironment: glioblastoma organoids as a study model., BP.PD; 22/08198-3 - Modulation of PrPC and CD44 expression in Glioblastoma stem-cells and its role on intracellular trafficking and vesicle biogenesis, BP.DD; 22/08106-1 - The role of extracellular vesicles of neural precursors in the PDX cells sensitivity to temozolomide, BP.MS; 21/13070-3 - Differential PrPC expression and correlated genes in patient-derived Glioblastoma stem cells and its consequence to the tumor maintenance and lineage commitment, BP.DD; 20/10671-3 - TMZ resistance in glioblastoma stem cells expressing distinct PrPc levels in normoxia and hypoxia culture conditions, BP.IC; 20/07450-5 - Evaluation of transcript levels of PrPc downstream targets and intracellular signaling pathways in glioblastoma stem cells, BP.IC; 20/04687-4 - The role of neural stem cells extracellular vesicles in the modulation of phenotype of PRNP low and PRNP high glioblastoma stem cells, BP.MS; 19/14952-0 - Characterization of intracellular signaling pathways modulated by the cellular prion protein on stemness maintenance in glioblastoma stem cells, BP.PD; 19/14552-1 - Analysis of differentially expressed genes in PRNPlow and PRNPhigh patient-derived glioblastoma stem cells, BP.IC; 19/14745-4 - Optimization of molecular approaches for validation of genes differentially expressed in PrPC-null cells, BP.TT; 19/12710-9 - Role of cellular prion protein in temozolomide resistance: emphasis on processes modulated by hypoxia, BP.PD; 19/11097-1 - Modulation of the neural phenotype of glioblastoma stem cells by extracellular miRNA from NSCs, BP.MS - associated scholarships

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

(8)

(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)

IGLESIA, REBECA PIATNICZKA; PRADO, MARIANA BRANDAO; ALVES, RODRIGO NUNES; ESCOBAR, MARIA ISABEL MELO; FERNANDES, CAMILA FELIX DE LIMA; FORTES, AILINE CIBELE DOS SANTOS; SOUZA, MARIA CLARA DA SILVA; BOCCACINO, JACQUELINE MARCIA; CANGIANO, GIOVANNI; SOARES, SAMUEL RIBEIRO; et al. Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 10, p. 17-pg., 2022-06-15. (21/05287-2, 21/13114-0, 18/15557-4, 19/14741-9, 19/11097-1, 20/03714-8, 20/04687-4, 19/12710-9, 17/26158-0, 20/07450-5, 19/06971-4, 20/05443-1, 21/13070-3)

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)

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)

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. (18/15557-4, 17/26158-0, 18/19320-9, 19/12710-9, 19/11097-1, 17/20271-0)

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)

PRADO, MARIANA B.; COELHO, BARBARA P.; IGLESIA, REBECA P.; ALVES, RODRIGO N.; BOCCACINO, JACQUELINE M.; FERNANDES, CAMILA F. L.; MELO-ESCOBAR, MARIA ISABEL; AYYADHURY, SHAMINI; CRUZ, MARIO C.; SANTOS, TIAGO G.; et al. Prion protein regulates invasiveness in glioblastoma stem cells. BMC CANCER, v. 24, n. 1, p. 17-pg., 2024-12-18. (19/14952-0, 20/07450-5, 17/26158-0, 20/03714-8, 19/11097-1, 18/15557-4, 17/20271-0, 18/19517-7, 19/14741-9, 19/12710-9, 22/08198-3)