PrPC and integrin α6 as pivotal molecules to orchestrate cell adhesion and ciliogenesis pathways in glioblastoma biology.

Author(s)

Maria Isabel Melo Escobar

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-05-06

Examining board members

Marilene Hohmuth Lopes; Vanessa Morais Freitas; Cibele Masotti; Maria Cristina Rodrigues Rangel

• Advisor: Marilene Hohmuth Lopes

Abstract

Glioblastoma (GBM), the most common primary malignant brain tumor, is dominated by Glioblastoma Stem Cells (GSCs) and characterized by cellular heterogeneity, limited response to therapy, and tumor recurrence. Cell-to-extracellular matrix interactions influence different signaling pathways that strongly determine the proliferation, differentiation, and migration of GBM cells. Integrins, important mediators of interaction between GBM cells and the surrounding microenvironment, share specific cell surface domains, such as lipid rafts, with the cellular prion protein (PrPC). PrPC is a cell surface glycoprotein, able to organize multiprotein complexes related to GSCs maintenance, of which integrin α6 (ITGA6) might participate towards integrated cell adhesion and cell signaling events in GBM cells. To investigate the potential association between PrPC and ITGA6 in GBMsamples, we combined in vitro experiments with both transcriptome and proteomic analyses to assess the modulation of expression of either PrPC or ITGA6 in GBM biology. Our results suggest that ITGA6 and PrPC modulate their expression mutually and are co-localized in GBM cells. Furthermore, ITGA6-knockdown GBM cells triggered upregulation of PrPC expression and vice-versa in U251 cells. Notably, transcriptome and proteome profiles analyses identified differentially expressed genes (DEGs) and proteins related to ciliogenesis (formation of a single and immobile membrane structure responsible for the control of different cellular phenomena) and cell adhesion processes in cells expressing high levels of ITGA6 and in PrPC knockout (PrPC-KO) GBM cells. Among the retrieved DEGs ITGA6, PRNP, PROM1, GLI1, PDGFRA, TUBA1A, and DNAHs pose as candidate interactors at the intersection of ciliogenesis and cell adhesion processes in GBM. Our findings reveal an emerging role for ITGA6 and PrPC in the ciliated state of GBM cells and may point out novel strategies to inhibit gliomagenesis. (AU)

• FAPESP's process: 19/11097-1 - Modulation of the neural phenotype of glioblastoma stem cells by extracellular miRNA from NSCs
• Grantee: Maria Isabel Melo Escobar
• Support Opportunities: Scholarships in Brazil - Master