Role of phosphoinositide 3-kinase δ in liver cell plasticity and its deregulation in hepatitis C virus-related pathogenesis

La plasticité épithéliale se manifeste par la transition épithélio-mésenchymateuse (EMT), un processus par lequel les cellules épithéliales changent leur polarité et leurs caractéristiques épithéliales pour adopter un phénotype mésenchymateux et peut-être associées au caractère souche. Dans cette étude, basée sur la culture d'organoïdes en 3D de lignées cellulaires dérivées du carcinome hépatocellulaire et sur la surexpression de la protéine par AAV8 dans le foie de souris, nous montrons que la modulation de l’activité de l’isoforme δ de la phosphoinositide 3-Kinase contrôle la différenciation cellulaire et permet la distinction entre le caractère souche et l’EMT en régulant la signalisation du TGFβ. Elle fournit ainsi un outil important pour contrôler le destin et la différenciation des cellules épithéliales et représente une avancée dans la compréhension du développement des carcinomes agressifs. D’autre part, on a de plus montré son rôle dans la régulation de la pathogenèse du VHC et le métabolisme lipidique par la signalisation Wnt/β-caténine.Epithelial plasticity is manifested by epithelial-mesenchymal transition (EMT), a process by which epithelial cells change their polarity and epithelial characteristics to adopt a mesenchymal phenotype and can be associated with stemness. In this study, based on 3D organoid culture of hepatocellular carcinoma-derived cell lines and AAV8-mediated overexpression of the protein in mouse liver, we show that modulation of mouse liver, we show that modulation of phosphoinositide 3-kinase (PI3Kδ) δ-isoform activity controls cell differentiation and allows the distinction between stemness and EMT by regulating TGFβ signaling. It thus provides an important tool to control epithelial cell fate (differentiation) and represents a breakthrough in understanding the development of aggressive carcinomas. On the other hand, its role in regulating HCV pathogenesis and lipid metabolism through Wnt/β-catenin signaling has been further demonstrated

PI3Kδ activity controls 1 plasticity and discriminates between EMT and stemness based on distinct TGF signalling

The stem cells involved in formation of the complex human body are epithelial cells that undergo apicobasal polarization and form a hollow lumen. Epithelial plasticity manifests as epithelial to mesenchymal transition (EMT), a process by which epithelial cells switch their polarity and epithelial features to adopt a mesenchymal phenotype. The connection between the EMT program and acquisition of stemness is now supported by a substantial number of reports, although what discriminates these two processes remains largely elusive. In this study, based on 3D organoid culture of hepatocellular carcinoma (HCC)-derived cell lines and AAV8-based protein overexpression in the mouse liver, we show that activity modulation of isoform δ of phosphoinositide 3-kinase (PI3Kδ) controls differentiation and discriminates between stemness and EMT by regulating the transforming growth factor (TGF) signalling. Thus, providing an important tool to control epithelial cell fate and represents a step forward in understanding the development of aggressive carcinoma

Intrinsic cancer cell phosphoinositide 3-kinase δ regulates fibrosis and vascular development in cholangiocarcinoma.

peer reviewed[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