Glioblastoma (GBM), or grade 4 glioma, represents the most aggressive and frequent form of primary brain tumour, with current treatments unable to overcome poor patient prognosis and tumour recurrence. This study investigates the cellular prion protein (PrPC) as a novel therapeutic target for GBM following observations in cancers, including glioma and GBM, that correlated increased PrPC expression with advanced tumour grade, worse prognosis, tumour recurrence and chemotherapeutic resistance. This may result from the perturbation of physiological PrPC functions that have been linked to cancer hallmarks. Analysis of RNA sequencing data from The Cancer Genome Atlas confirmed previous findings that high PRNP expression correlates with worsened survival in human GBM patients, whereas PRNP expression was observed to decrease with increasing glioma grade.
To investigate the role of PrPC in cancer progression, varied expression of the PrPC gene (Prnp) was established in a glioma mouse model involving activation of the PI3K/Akt pathway via expression of a Pik3caH1047R oncogenic mutation and deletion of the PtenΔ tumour suppressor gene.
Whilst Prnp+/+Pik3caH1047R/H1047RPtenΔ mice with wild-type PrPC expression developed GBM tumours as previously observed, reduced PrPC expression in Prnp+/-Pik3caH1047R/H1047RPtenΔ mice induced lower-grade tumours or hypercellularity in the absence of tumours. Interestingly, in the absence of PrPC expression, Prnp-/-Pik3caH1047R/H1047RPtenΔ mice produced GBM-like tumours, that appeared less invasive with reduced cellularity relative to Prnp+/+Pik3caH1047R/H1047RPtenΔ mice. Tumour pathology coincided with survival of mice, with Prnp+/+Pik3caH1047R/H1047RPtenΔ mice exhibiting significantly worsened survival, relative to Prnp-/-Pik3caH1047R/H1047RPtenΔ and Prnp+/-Pik3caH1047R/H1047RPtenΔ mice, consistent with in-silico observations. These findings suggest that modulation of PrPC expression influences GBM progression.
The role of PrPC in GBM hallmark development, including proliferation, survival, stemness and invasion, will be interrogated in-vitro within neural stem/progenitor cells (NSPCs), isolated from Prnp+/+, Prnp+/- and Prnp-/- Pik3caH1047R/H1047RPtenΔ mice. Understanding the role of novel factors such as PrPC in GBM may provide the basis for novel therapeutic strategies to complement current ineffective treatments.