The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancer
Open accessAbstract
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.
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The concentration of soluble TGFβ in the supernatant of colon cancer cells is partly controlled by the cellular prion protein PrPC.
“we recently brought some insight into this issue by showing that the concentration of soluble TGFβ in the supernatant of colon cancer cells is partly controlled by the cellular prion protein PrPC (35).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [35]
CMS4-like colon cancer cells themselves respond to TGFβ and control the expression of a number of CMS4-specific genes through this pathway.
“we reported that CMS4-like colon cancer cells themselves respond to TGFβ, and notably control the expression of a number of CMS4-specific genes through this pathway (35).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [35]
PrPC controls the expression of many CMS4-specific genes in colon cancer cells through diverse signaling intermediates.
“we introduced PrPC, a plasma membrane-tethered protein endowed with the capacity to participate in signal transduction events (38), as a key protagonist of CMS4 colon cancer, controlling the expression of many CMS4-specific genes in colon cancer cells through diverse signaling intermediates (35, 39).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [35]
PrPC is elevated in plasma derived from patients with metastatic colorectal cancer.
“and elevated in plasma derived from patients with metastatic colorectal cancer (35).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [35]
TGFβ and Kynurenine are involved in the immunotolerant CMS4 tumor microenvironment.
“Regarding the immunotolerant CMS4 TME, we posit an involvement of TGFβ (56) and Kynurenine (57), both produced by cancer cells under the control of PrPC (35, 39)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [35]
PrPC is increased in CMS4 tumors.
“One candidate circulating biomarker is PrPC, which we found to be increased in CMS4 tumors”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [35]
CMS4 is associated with a TIC-like and/or epithelial-mesenchymal transition (EMT) signature.
“and a TIC-like and/or epithelial-mesenchymal transition (EMT) signature (Le Corre et al., 2019)”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Le Corre et al., 2019
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Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer
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- Authors
- Le Corre, D., Ghazi, A., Balogoun, R., Pilati, C., Aparicio, T., Martin-Lannerée, S., Marisa, L., Djouadi, F., Poindessous, V., Crozet, C., Emile, J.-F., Mulot, C., Le Malicot, K., Boige, V., Blons, H., de Reynies, A., Taieb, J., Ghiringhelli, F., Bennouna, J., Launay, J.-M., Laurent-Puig, P., & Mouillet-Richard, S.
- Affiliations
- Inserm (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Université de Montpellier (FR)
- Hôpital Ambroise-Paré (FR)
- Centre Georges François Leclerc (FR)
- Institut de Cancérologie de l'Ouest (FR)
- F. Hoffmann-La Roche AG (CH)
- ORCID
- Venue
- eBioMedicine
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 46
- Pages
- 94-104
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC6710984
- OpenAlex
- W2965280403
- Cited by
- 48
- References
- 42
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 13 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 5 · 2019: 2
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Association pour la Recherche sur le Cancer (PJA 20171206220)
- Institut National de la Santé et de la Recherche Médicale
- Institut National Du Cancer
- Cancéropôle Ile de France (2016-1-EMERG-36-UP 5-1, 415)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- cellular prion protein, prion protein gene, colorectal cancer, cancer stemness, Hippo signaling pathway, YAP, TAZ, TGF-beta signaling, metastatic colorectal cancer, prognostic factors, disease outcome
- MeSH terms
- Prion Proteins, Hippo Signaling Pathway, Adult, Aged, Aged, 80 and over, Animals, Female, Humans, Male, Middle Aged, Prognosis, RNA, Messenger, Colorectal Neoplasms, Signal Transduction, Biomarkers, Gene Expression, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Cell Line, Tumor, Kaplan-Meier Estimate, Epithelial-Mesenchymal Transition
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