Search

Background: Glioblastoma (GBM) is an aggressive brain tumor that exhibits resistance to current treatment, making the identification of novel therapeutic targets essential. In this context, cellular prion protein (PrP C ) stands out as a potential candidate for new therapies. Encoded by the PRNP gene, PrP C can present increased expression levels in GBM, impacting cell proliferation, growth, migration, invasion and stemness. Nevertheless, the exact molecular mechanisms through which PRNP/PrP C modulates key aspects of GBM biology remain elusive., Methods: To elucidate the implications of PRNP/PrP C in the biology of this cancer, we analyzed publicly available RNA sequencing (RNA-seq) data of patient-derived GBMs from four independent studies. First, we ranked samples profiled by bulk RNA-seq as PRNP high and PRNP low and compared their transcriptomic landscape. Then, we analyzed PRNP + and PRNP - GBM cells profiled by single-cell RNA-seq to further understand the molecular context within which PRNP/PrP C might function in this tumor. We explored an additional proteomics dataset, applying similar comparative approaches, to corroborate our findings., Results: Functional profiling revealed that vesicular dynamics signatures are strongly correlated with PRNP/PrP C levels in GBM. We found a panel of 73 genes, enriched in vesicle-related pathways, whose expression levels are increased in PRNP high /PRNP + cells across all RNA-seq datasets. Vesicle-associated genes, ANXA1, RAB31, DSTN and SYPL1, were found to be upregulated in vitro in an in-house collection of patient-derived GBM. Moreover, proteome analysis of patient-derived samples reinforces the findings of enhanced vesicle biogenesis, processing and trafficking in PRNP high /PRNP + GBM cells., Conclusions: Together, our findings shed light on a novel role for PrP C as a potential modulator of vesicle biology in GBM, which is pivotal for intercellular communication and cancer maintenance. We also introduce GBMdiscovery, a novel user-friendly tool that allows the investigation of specific genes in GBM biology., (© 2024. The Author(s).)