A proof of concept for targeting the PrP(C) - Amyloid β peptide interaction in basal prostate cancer and mesenchymal colon cancer

The cellular prion protein PrP(C) partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrP(C) and CAV1 across cancer. Using cell-based assays, we show that PrP(C) regulates the expression of and interacts with CAV1. PrP(C) additionally controls the expression of the amyloid precursor protein APP and of the Aβ generating enzyme BACE1, and regulates the levels of Aβ, whose accumulation is a central event in Alzheimer’s disease. We further identify DKK1 and DKK3, involved in both Alzheimer’s disease and cancer progression, as targets of the PrP(C)-dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrP(C) interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aβ-PrP(C)-dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aβ-PrP(C) axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer.