A proof of concept for targeting the PrPC - Amyloid β peptide interaction in basal prostate cancer and mesenchymal colon cancer

Abstract

The cellular prion protein PrPC 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 PrPC and CAV1 across cancer. Using cell-based assays, we show that PrPC regulates the expression of and interacts with CAV1. PrPC 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 PrPC-dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrPC 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-PrPC-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-PrPC axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer.

Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer

“…From the above data, we may hypothesize that, in CRC patients, β-catenin and glucocorticoid pathway activation cooperatively induce PRNP expression and may, as a consequence, instigate a detrimental vicious circle. Accordingly and in line with our previous findings [ 9 , 10 ] and those illustrated in Fig. 2 G and 3 G, PRNP , BACE1 , DKK3 , PDGFC , NR3C1 and TSC22D3 levels were all enriched in the CMS4 subgroups of tumors from the IDEA France cohort (Fig.…”

“…Elevated expression of PRNP in homozygous mice (Additional file 1 : Fig. S4A) was accompanied by increased expression of a set of genes that we previously identified as PrP C gene targets in colon cancer cells [ 10 ], namely App , Bace1 , Dkk3 , Pdgfc and Tgfb1 (Additional file 1 : Fig. S4B–F), thus validating our model as a robust PRNP -overexpressing paradigm.…”

“…According to our previous findings and the above data, PrP C sustains positive feedback loops with multiple effectors in colon cancer cells: TGFβ1 [ 9 ], but also the integrin linked kinase (ILK) [ 32 ], the amyloid precursor protein (APP)-derived Aβ [ 10 ], or the GR (cf above). This prompted us to investigate whether this would also apply to the Wnt pathway.…”

“…8 ) We have recently documented that PrP C is overexpressed in the mesenchymal, poor-prognosis subtype of CRC, and have shed some mechanistic insight into how it contributes to the mesenchymal phenotype of CRC cells [ 9 , 32 ]. Going one step further, we have provided the proof of concept that antibody-mediated neutralization of PrP C may represent a novel therapeutic strategy to target mesenchymal CRC [ 10 ]. However, an integrated view of the mechanisms leading to the upregulation of PrP C was lacking.…”

“…These pathways are well known to crosstalk with Wnt-β-catenin signaling [ 8 ], and, therefore, are good candidates for influencing the Wnt-β-catenin output. Recently, we documented that the cellular prion protein PrP C , encoded by the PRNP gene, is an upstream regulator of these two major pathways in CMS4 CRC [ 9 ], and that its targeting is a promising approach to treat CMS4 patients [ 10 ]. Long confined to the field of neurodegenerative diseases, PrP C is now attracting a great deal of interest in cancer research [ 11 ].…”