Background: Increased expression of the cellular prion protein (PrPC) in glioblastoma (GBM) tumours is associated with poor patient prognosis. The perturbation of several physiological functions of PrPC have also been linked to the hallmarks of cancer. However, the contribution of PrPC expression to tumour initiation and progression has not been established.
Aim: To investigate the effect of PrPC expression on tumour progression using low- and high-grade glioma clinical data and mouse models.
Methods: PrPC gene (PRNP) expression was correlated with patient clinical progression in The Cancer Genome Atlas (TCGA) low-grade glioma (LGG) and GBM RNA-sequencing datasets. Knockout (KO) and wild-type (WT) expression of the PrPC gene (Prnp) was established in a low- and high-grade (GBM) glioma mouse model targeting the PI3K/Akt pathway through Cre-recombinase inducible expression of the Pik3caH1047R oncogenic mutant and/or deletion of the tumour suppressor gene Pten in neural stem cells (NSCs). The effect of PrPC on cancer cell biology was assessed in vivo in mice 6 weeks after tumour induction and in vitro in isolated NSCs.
Results and discussion: In patients with GBM, reduced PRNP expression was associated with improved survival, which was reflected in vitro by decreased proliferation of NSCs derived from PrPC KO GBM (Pik3ca-Pten) mice. In contrast, in patients with LGG, reduced PRNP expression was associated with poor survival. Additionally, PrPC ablation (KO) in the LGG (Pten) model enhanced NSC proliferation, stemness and invasion in vitro and increased tumour size in vivo. This was corroborated by preliminary data showing that PrPC overexpression using a lentiviral transduction system in PrPC KO LGG (Pten) NSCs reduced cell proliferation and stemness.
Conclusions: Clinical data, in vitro and in vivo models of glioma indicate that PrPC has a differential effect on tumour biology that is contingent on genetic context or disease progression. Ongoing spatial transcriptomics analysis of tumours will inform the role of PrPC expression in cancer. This may provide the basis for the development of novel biomarkers or therapeutics to complement current glioma treatments.