Figure 3 from <i>In Vivo</i> Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma
<p><i>Nf2</i> loss results in Ras<sup>G12D</sup>-induced oncogenesis and cooperates with <i>Trp53</i> loss to accelerate ICC formation. <b>A,</b> Kaplan–Meier curve demonstrating the relative survival proportions of mice with KRAS<sup>G12D&...
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2025
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| Sumario: | <p><i>Nf2</i> loss results in Ras<sup>G12D</sup>-induced oncogenesis and cooperates with <i>Trp53</i> loss to accelerate ICC formation. <b>A,</b> Kaplan–Meier curve demonstrating the relative survival proportions of mice with KRAS<sup>G12D</sup> and gRNAs targeting <i>Trp53</i> (<i>N</i> = 12), <i>Nf2</i> (<i>N</i> = 5), <i>Nf2</i>;<i>Trp53</i> (<i>N</i> = 13), or nontargeting control (scrm, <i>N</i> = 5). <b>B</b> and <b>C,</b> Proportion of liver occupied by tumor (<b>B</b>) and number of tumors per mouse (<b>C</b>). <b>D,</b> Hematoxylin and eosin (H&E) staining of KRAS<sup>G12D</sup> tumors with <i>Trp53</i>, <i>Nf2</i>, or <i>Trp53</i>;<i>Nf2</i> loss. Scale bar, 100 μm. Dotted line, tumor-stroma boundary. <b>E,</b> Comparison of RNA-seq analysis when the transcriptomes from <i>Nf2</i>;<i>Trp53</i> versus <i>Trp53</i> alone tumors (blue) are compared with transcripts from <i>Nf2</i>;<i>Trp53</i> versus <i>Nf2</i> alone (yellow) tumors. Each group contains <i>N</i> = 4 regionally distinct tumors. <b>F,</b> Analysis of RPPA data demonstrating the changes in the proportion of phosphorylated GSK3α/β, β-catenin, and pAKT relative to total protein levels in KRAS<sup>G12D</sup>;<i>Trp53</i><sup>KO</sup> (gray points), KRAS<sup>G12D</sup>;<i>Nf2</i><sup>KO</sup> (yellow points), KRAS<sup>G12D</sup>;<i>Trp53</i><sup>KO</sup>;<i>Nf2</i><sup>KO</sup> (blue points). <b>G,</b> IHC of active, dephosphorylated β-catenin (top) and phosphorylated AKT<sup>Ser647</sup> (bottom) in KRAS<sup>G12D</sup>;<i>Trp53</i><sup>KO</sup>, KRAS<sup>G12D</sup>;<i>Nf2</i><sup>KO</sup>, KRAS<sup>G12D</sup>;<i>Trp53</i><sup>KO</sup>/<i>Nf2</i><sup>KO</sup> tumors. Scale bar, 50 μm. <b>H.</b> Immunoblot for dephosphorylated (active) β-catenin (β-catenin<sup>Ser33/37/Thr41</sup>) in tumors isolated from mice baring Kras<sup>G12D</sup> -driven ICC with <i>Trp53</i>, <i>Nf2</i>, or <i>Trp53</i>;<i>Nf2</i> co-loss. GAPDH was used as a loading control. <b>I,</b> Schematic representing our dosing approach to determine whether Wnt inhibition, PI3K inhibition, or a combination of the two is effective in improving the survival of mice with KRAS<sup>G12D</sup>;<i>Trp53</i><sup>KO</sup>;<i>Nf2</i><sup>KO</sup> ICC. <b>J,</b> Kaplan–Meier curve demonstrating the survival changes when KRAS<sup>G12D</sup>;<i>Trp53</i><sup>KO</sup>;<i>Nf2</i><sup>KO</sup> animals are treated with vehicle (yellow line), LGK974 (Wnt-inhibitor; blue line), pictilisib (PI3K inhibitor; orange line), or a combination (green line; <i>N</i> = 5 per group).</p> |
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