The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context
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 t...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-08-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419304785 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Delphine Le Corre Alexandre Ghazi Ralyath Balogoun Camilla Pilati Thomas Aparicio Séverine Martin-Lannerée Laetitia Marisa Fatima Djouadi Virginie Poindessous Carole Crozet Jean-François Emile Claire Mulot Karine Le Malicot Valérie Boige Hélène Blons Aurélien de Reynies Julien Taieb François Ghiringhelli Jaafar Bennouna Jean-Marie Launay Pierre Laurent-Puig Sophie Mouillet-Richard |
| spellingShingle |
Delphine Le Corre Alexandre Ghazi Ralyath Balogoun Camilla Pilati Thomas Aparicio Séverine Martin-Lannerée Laetitia Marisa Fatima Djouadi Virginie Poindessous Carole Crozet Jean-François Emile Claire Mulot Karine Le Malicot Valérie Boige Hélène Blons Aurélien de Reynies Julien Taieb François Ghiringhelli Jaafar Bennouna Jean-Marie Launay Pierre Laurent-Puig Sophie Mouillet-Richard The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context EBioMedicine |
| author_facet |
Delphine Le Corre Alexandre Ghazi Ralyath Balogoun Camilla Pilati Thomas Aparicio Séverine Martin-Lannerée Laetitia Marisa Fatima Djouadi Virginie Poindessous Carole Crozet Jean-François Emile Claire Mulot Karine Le Malicot Valérie Boige Hélène Blons Aurélien de Reynies Julien Taieb François Ghiringhelli Jaafar Bennouna Jean-Marie Launay Pierre Laurent-Puig Sophie Mouillet-Richard |
| author_sort |
Delphine Le Corre |
| title |
The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context |
| title_short |
The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context |
| title_full |
The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context |
| title_fullStr |
The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context |
| title_full_unstemmed |
The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context |
| title_sort |
cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerresearch in context |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2019-08-01 |
| description |
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 PrPC 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 PrPC-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 PrPC function on markers of the mesenchymal subtype and to delineate the signalling pathways recruited by PrPC. We measured soluble PrPC 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 PrPC 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 PrPC are elevated in metastatic CRC and are associated with poor disease control. Interpretation: Our findings define PrPC as a candidate driver of the poor-prognosis mesenchymal subtype of CRC. They suggest that PrPC 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. Keywords: Colorectal cancer, Molecular classification, Prion protein, Hippo pathway, TGFß pathway |
| url |
http://www.sciencedirect.com/science/article/pii/S2352396419304785 |
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doaj-40447755c68848f595bfc79fb34694ff2020-11-25T01:28:33ZengElsevierEBioMedicine2352-39642019-08-014694104The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in contextDelphine Le Corre0Alexandre Ghazi1Ralyath Balogoun2Camilla Pilati3Thomas Aparicio4Séverine Martin-Lannerée5Laetitia Marisa6Fatima Djouadi7Virginie Poindessous8Carole Crozet9Jean-François Emile10Claire Mulot11Karine Le Malicot12Valérie Boige13Hélène Blons14Aurélien de Reynies15Julien Taieb16François Ghiringhelli17Jaafar Bennouna18Jean-Marie Launay19Pierre Laurent-Puig20Sophie Mouillet-Richard21Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceDepartment of Gastroenterology and Digestive Oncology, AP-HP, Hôpital Saint-Louis, Université Paris Diderot, F-75010 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceProgramme ''Cartes d'Identité des Tumeurs'', Ligue Nationale Contre le Cancer, F-75013 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceInstitut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Université de Montpellier UMR-1183, Centre Hospitalo-Universitaire de Montpellier, F-34000 Montpellier, FranceDepartment of Pathology, AP-HP, Hôpital Ambroise Paré, F-92100 Boulogne-Billancourt, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, FranceFédération Francophone de Cancérologie Digestive, EPICAD INSERM LNC-UMR 1231, Université de Bourgogne et and Franche Comté, F-21000 Dijon, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France; Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Saclay, F-94800 Villejuif, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France; Department of Biology, AP-HP, Hôpital Européen Georges Pompidou, F-75015 Paris, FranceProgramme ''Cartes d'Identité des Tumeurs'', Ligue Nationale Contre le Cancer, F-75013 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France; Department of Gastroenterology and GI Oncology, AP-HP, Hôpital Européen Georges Pompidou, F-75015 Paris, FranceDepartment of Medical Oncology, Centre Georges-François Leclerc, F-21000 Dijon, FranceDepartment of Medical Oncology, Institut de Cancérologie de l'Ouest, F-44800 Saint-Herblain, FranceDepartment of Biochemistry and Molecular Biology, INSERM U942, AP-HP, Hôpital Lariboisière, Université Paris Descartes, F-75010 Paris, France; Pharma Research Department, F. Hoffmann-La-Roche Ltd., CH-4070 Basel, SwitzerlandCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France; Department of Biology, AP-HP, Hôpital Européen Georges Pompidou, F-75015 Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France; Corresponding author at: INSERM UMR-S 1138, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, 15 rue de l'Ecole de Médecine, F-75006 Paris, France.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 PrPC 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 PrPC-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 PrPC function on markers of the mesenchymal subtype and to delineate the signalling pathways recruited by PrPC. We measured soluble PrPC 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 PrPC 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 PrPC are elevated in metastatic CRC and are associated with poor disease control. Interpretation: Our findings define PrPC as a candidate driver of the poor-prognosis mesenchymal subtype of CRC. They suggest that PrPC 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. Keywords: Colorectal cancer, Molecular classification, Prion protein, Hippo pathway, TGFß pathwayhttp://www.sciencedirect.com/science/article/pii/S2352396419304785 |