The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancer

BACKGROUND: Comprehensive transcriptomic analyses have shown that colorectal cancer (CRC) is heterogeneous and have led to the definition of molecular subtypes among which the stem-cell, mesenchymal-like group is associated with poor prognosis. The molecular pathways orchestrating the emergence of this subtype are incompletely understood. In line with the contribution of the cellular prion protein PrP(C) to stemness, we hypothesize that deregulation of this protein could lead to a stem-cell, mesenchymal-like phenotype in CRC. METHODS: We assessed the distribution of the PrP(C)-encoding PRNP mRNA in two large CRC cohorts according to molecular classification and its association with patient survival. We developed cell-based assays to explore the impact of gain and loss of PrP(C) function on markers of the mesenchymal subtype and to delineate the signalling pathways recruited by PrP(C). We measured soluble PrP(C) in the plasmas of 325 patients with metastatic CRC and probed associations with disease outcome. FINDINGS: We found that PRNP gene expression is enriched in tumours of the mesenchymal subtype and is associated with poor survival. Our in vitro analyses revealed that PrP(C) controls the expression of genes that specify the mesenchymal subtype through the recruitment of the Hippo pathway effectors YAP and TAZ and the TGFß pathway. We showed that plasma levels of PrP(C) are elevated in metastatic CRC and are associated with poor disease control. INTERPRETATION: Our findings define PrP(C) as a candidate driver of the poor-prognosis mesenchymal subtype of CRC. They suggest that PrP(C) may serve as a potential biomarker for patient stratification in CRC. FUNDING: Grant support was provided by the following: Cancéropôle Ile de France (grant number 2016-1-EMERG-36-UP 5-1), Association pour la Recherche sur le Cancer (grant number PJA 20171206220), SATT Ile de France Innov (grant number 415) as well as INSERM.