Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer
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Published:2024-04-08
Issue:1
Volume:22
Page:
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ISSN:1479-5876
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Container-title:Journal of Translational Medicine
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language:en
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Short-container-title:J Transl Med
Author:
Mouillet-Richard SophieORCID, Gougelet Angélique, Passet Bruno, Brochard Camille, Le Corre Delphine, Pitasi Caterina Luana, Joubel Camille, Sroussi Marine, Gallois Claire, Lavergne Julien, Castille Johan, Vilotte Marthe, Daniel-Carlier Nathalie, Pilati Camilla, de Reyniès Aurélien, Djouadi Fatima, Colnot Sabine, André Thierry, Taieb Julien, Vilotte Jean-Luc, Romagnolo Béatrice, Laurent-Puig Pierre
Abstract
Abstract
Background
The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC.
Methods
We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients.
Results
In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence.
Conclusions
An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.
Funder
Cancéropôle Ile de France Association pour la Recherche sur le Cancer SIRIC CARPEM Labex Immuno-Oncology GEMLUC Inserm INRAE Plan cancer Agence Nationale de la Recherche Ligue Contre le Cancer Fondation pour la Recherche Médicale
Publisher
Springer Science and Business Media LLC
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