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. 2022 Jan 24;82(8):1548–1559. doi: 10.1158/0008-5472.CAN-21-2556

Figure 4.

Figure 4. Therapeutic coinhibition of Wnt and PI3K signaling reduces tumor growth in ICC. A, RNA-seq data of human ICC demonstrating a positive correlation between the activity of canonical Wnt signaling and Akt signaling. B, Schematic representation of the KPPTom cholangiocarcinoma model where CreERT expression in Keratin-19–positive cholangiocytes results in the inactivation of Trp53 and Pten, whereas labeling transformed cells with tdTomato. C, Representative IHC staining of KPPTom model following tamoxifen administration (day 0) and following 4 and 8 weeks of thioacetamide administration. tdTomato (red) denotes recombined cholangiocytes (denoted by Keratin-19; green). Blue, DNA. Top, whole mount FUNGI images; bottom, 2D histologic sections. Scale bar, 200 μm. White arrows, tdTomato-positive cells. D, Quantification of liver tissue occupied by tumor in the KPPTom ICC model. E, IHC showing that KPPTom ICC has activated canonical Wnt signaling [by staining for dephosphorylated (active) β-catenin] and PI3K activity (through pAKTSer647 positivity). Red arrows, positive cells. Scale bar, 100 μm. F, A schematic representation of how the KPPTom model was used to test the effectiveness of Wnt and Pi3K inhibitor combinations on ICC progression. G, IHC staining for tdTomato-positive cancer cells in vehicle-treated animals compared with those treated with a combination of LGK974 and pictilisib. Scale bar, 100 μm. H, Number of tdTomato-positive cells in KPPTom animals given vehicle or LGK974 and pictilisib in combination. I, Proportion of KPPTom animals containing macroscopic tumors in KPPTom animals treated with vehicle versus combination treatment. b.d., bile duct; p.v., portal vein.

Therapeutic coinhibition of Wnt and PI3K signaling reduces tumor growth in ICC. A, RNA-seq data of human ICC demonstrating a positive correlation between the activity of canonical Wnt signaling and Akt signaling. B, Schematic representation of the KPPTom cholangiocarcinoma model where CreERT expression in Keratin-19–positive cholangiocytes results in the inactivation of Trp53 and Pten, whereas labeling transformed cells with tdTomato. C, Representative IHC staining of KPPTom model following tamoxifen administration (day 0) and following 4 and 8 weeks of thioacetamide administration. tdTomato (red) denotes recombined cholangiocytes (denoted by Keratin-19; green). Blue, DNA. Top, whole mount FUNGI images; bottom, 2D histologic sections. Scale bar, 200 μm. White arrows, tdTomato-positive cells. D, Quantification of liver tissue occupied by tumor in the KPPTom ICC model. E, IHC showing that KPPTom ICC has activated canonical Wnt signaling [by staining for dephosphorylated (active) β-catenin] and PI3K activity (through pAKTSer647 positivity). Red arrows, positive cells. Scale bar, 100 μm. F, A schematic representation of how the KPPTom model was used to test the effectiveness of Wnt and Pi3K inhibitor combinations on ICC progression. G, IHC staining for tdTomato-positive cancer cells in vehicle-treated animals compared with those treated with a combination of LGK974 and pictilisib. Scale bar, 100 μm. H, Number of tdTomato-positive cells in KPPTom animals given vehicle or LGK974 and pictilisib in combination. I, Proportion of KPPTom animals containing macroscopic tumors in KPPTom animals treated with vehicle versus combination treatment. b.d., bile duct; p.v., portal vein.