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We reported that the isoform \u03b4 (PI3K\u03b4) 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Approach &amp; Results<\/jats:title><jats:p>Immunohistochemical analyses of CCA samples reveal a high expression of PI3K\u03b4 in the less differentiated CCA. The RT\u2010qPCR and immunoblot analyses performed on CCA cells stably overexpressing PI3K\u03b4 using lentiviral construction reveal an increase of mesenchymal and stem cell markers and the pluripotency transcription factors. CCA cells stably overexpressing PI3K\u03b4 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 PI3K\u03b4\u2010overexpressing 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\u2010based\u2010PI3K\u03b4 overexpression. These PI3K\u03b4\u2010mediated cell morphogenesis and stroma remodelling were dependent on TGF\u03b2\/Src\/Notch signalling. Whole transcriptome analysis of PI3K\u03b4 using the cancer cell line encyclopedia allows the classification of CCA cells according to cancer progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Overall, our results support the critical role of PI3K\u03b4 in the progression and aggressiveness of CCA via TGF\u03b2\/src\/Notch\u2010dependent mechanisms and open new directions for the classification and treatment of CCA patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15751","type":"journal-article","created":{"date-parts":[[2023,10,8]],"date-time":"2023-10-08T18:38:56Z","timestamp":1696790336000},"page":"2776-2793","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Intrinsic cancer cell phosphoinositide 3\u2010kinase \u03b4 regulates fibrosis and vascular development in 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