[en] [en] BACKGROUND & AIMS: The class I- phosphatidylinositol-3 kinases (PI3Ks) signalling is dysregulated in almost all human cancers whereas the isoform-specific roles remain poorly investigated. We reported that the isoform δ (PI3Kδ) regulated epithelial cell polarity and plasticity and recent developments have heightened its role in hepatocellular carcinoma (HCC) and solid tumour progression. However, its role in cholangiocarcinoma (CCA) still lacks investigation.
APPROACH & RESULTS: Immunohistochemical analyses of CCA samples reveal a high expression of PI3Kδ in the less differentiated CCA. The RT-qPCR and immunoblot analyses performed on CCA cells stably overexpressing PI3Kδ using lentiviral construction reveal an increase of mesenchymal and stem cell markers and the pluripotency transcription factors. CCA cells stably overexpressing PI3Kδ cultured in 3D culture display a thick layer of ECM at the basement membrane and a wide single lumen compared to control cells. Similar data are observed in vivo, in xenografted tumours established with PI3Kδ-overexpressing CCA cells in immunodeficient mice. The expression of mesenchymal and stemness genes also increases and tumour tissue displays necrosis and fibrosis, along with a prominent angiogenesis and lymphangiogenesis, as in mice liver of AAV8-based-PI3Kδ overexpression. These PI3Kδ-mediated cell morphogenesis and stroma remodelling were dependent on TGFβ/Src/Notch signalling. Whole transcriptome analysis of PI3Kδ using the cancer cell line encyclopedia allows the classification of CCA cells according to cancer progression.
CONCLUSIONS: Overall, our results support the critical role of PI3Kδ in the progression and aggressiveness of CCA via TGFβ/src/Notch-dependent mechanisms and open new directions for the classification and treatment of CCA patients.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bou Malham, Vanessa ; INSERM, Unité 1193, Villejuif, France ; Université Paris-Saclay, UMR-S 1193, Villejuif, France
Benzoubir, Nassima; INSERM, Unité 1193, Villejuif, France ; Université Paris-Saclay, UMR-S 1193, Villejuif, France
Vaquero, Javier; Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France ; Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
Desterke, Christophe; Université Paris-Saclay, UFR Médecine-INSERMS1310, Villejuif, France
Agnetti, Jean; INSERM, Unité 1193, Villejuif, France ; Université Paris-Saclay, UMR-S 1193, Villejuif, France
Song, Pei Xuan; INSERM, Unité 1193, Villejuif, France ; Université Paris-Saclay, UMR-S 1193, Villejuif, France
Gonzalez-Sanchez, Ester ; Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France ; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain ; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain ; Inovarion, Paris, France
Arbelaiz, Ander; Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France
Jacques, Sophie ; Université de Liège - ULiège > GIGA > GIGA Medical Genomics - Unit of Animal Genomics
Di Valentin, Emmanuel ; Université de Liège - ULiège > GIGA > GIGA Platform Viral vectors ; Université de Liège - ULiège > Département des sciences de la vie > Virologie - Immunologie
Rahmouni, Souad ; Université de Liège - ULiège > GIGA > GIGA Medical Genomics - Unit of Animal Genomics
Tan, Tuan Zea; Genomics and Data Analytics Core (GeDaC), Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Samuel, Didier ; INSERM, Unité 1193, Villejuif, France ; Université Paris-Saclay, UMR-S 1193, Villejuif, France ; Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Villejuif, France
Thiery, Jean Paul; Guangzhou Laboratory, International Biological Island Guangzhou, Guangzhou, China
Sebagh, Mylène ; INSERM, Unité 1193, Villejuif, France ; Université Paris-Saclay, UMR-S 1193, Villejuif, France ; Laboratoire d'Anatomopathologie, AP-HP Hôpital Paul-Brousse, Villejuif, France
Fouassier, Laura ; Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France
Gassama-Diagne, Ama ; INSERM, Unité 1193, Villejuif, France ; Université Paris-Saclay, UMR-S 1193, Villejuif, France
INSERM - Institut National de la Santé et de la Recherche Médicale [FR] FRM - Fondation pour la Recherche Médicale [FR] AEEH - Asociación Española para el Estudio del Hígado [ES]
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