A proof of concept for targeting the PrPC - Amyloid β peptide interaction in basal prostate cancer and mesenchymal colon cancer
Open accessAbstract
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.
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Neutralizing antibodies against PrPC reduced expression of CMS4 genes and soluble TGFβ levels in preclinical models.
“| PrPC | Neutralizing antibodies | Reduced expression of CMS4 genes and soluble TGFβ levels | (68) |”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [68]
PrPC neutralization could have the combined advantage of reducing both TGFβ and PDGF signaling.
“or PrPC, whose neutralization could have the combined advantage of reducing both TGFβ and PDGF signaling (68).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [68]
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- Authors
- Mouillet-Richard, S., Martin-Lannerée, S., Le Corre, D., Hirsch, T. Z., Ghazi, A., Sroussi, M., Pilati, C., de Reyniès, A., Djouadi, F., Vodovar, N., Launay, J.-M., & Laurent-Puig, P.
- Affiliations
- Inserm (FR)
- F. Hoffmann-La Roche AG (CH)
- ORCID
- Venue
- Oncogene
- Published
- 2022-08-12
- Volume
- 41
- Issue
- 38
- Pages
- 4397-4404
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC9481457
- OpenAlex
- W4291145333
- Cited by
- 14
- References
- 33
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 4
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Oncogene (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer (PJA 20171206220)
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale (FDM202006011237)
- Institut National Du Cancer
- Cancéropôle Ile de France (2016-1-EMERG-36-UP 5-1)
- Direction Générale de l’offre de Soins
- Groupement des Entreprises Françaises dans la lutte contre le Cancer
- Société d'Accélération du Transfert de Technologies
- Labex Immuno-Oncology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Keywords
- cellular prion protein, caveolin-1, amyloid-beta, amyloid precursor protein, BACE1, DKK1, DKK3, metastasis, Alzheimer's disease, cancer therapy targets
- MeSH terms
- Prion Proteins, Alzheimer Disease, Colonic Neoplasms, Humans, Male, Prostatic Neoplasms, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Caveolin 1, Amyloid Precursor Protein Secretases
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