Figure 8.
SIRT1 silencing or pharmacological inhibition reverts NEPC. (A–G)Sirt1 silencing in a mouse organoid model of NEPC. (A) Schematic representation showing mouse NEPC organoids treated with shRNAs targeting Sirt1 and subjected to in vitro and in vivo analyses. (B) Shown are images of allografted tumors from the indicated groups imaged at the time of euthanasia (n = 6/group). (C) Representative images of allografted tumors grown from organoids (n = 6/group). Shown are H&E and immunostaining for AR, PanCK, Vimentin (Vim), Insm1, and synaptophysin (Syp). Scale bar = 50 μm. (D) Tumor volume measurements for the indicated groups. N = 6/group. P value was calculated using a two-way ANOVA test. (E) Bar plot with overlaid dots showing the tumor weight (g) for the indicated groups of mice (n = 6/group). P value was calculated using the Welch’s two sample t test. (F) Representative images of organoids from the indicated groups (n = 6/group). Shown are H&E and immunostaining for the indicated markers. Scale bar = 20 μm. (G) Heatmap representation of relative expression levels of the Sirt1, Ar, and the indicated markers of NEPC. (H and I) Pharmacological inhibition of Sirt1 in mouse NEPC organoids. (H) Schematic representation showing mouse NEPC organoids treated with the SIRT1 inhibitor Selisistat. (I) Heatmap representation of relative expression levels of Sirt1, Ar, and the indicated markers of NEPC for the indicated groups of organoids. Experiments were performed in quadruplicate and with a minimum of two independent biological replicates. See also Fig. S5. Refer to the image caption for details. Panel A shows schematic strategy for Sirt1 suppression in mouse NEPC organoids. Panel B shows images comparing allografted tumors from shControl and shSirt1 groups. Panel C shows histological and immunostained allografted tumor sections from indicated groups. Panel D shows line graph comparing tumor volume progression between experimental groups. Panel E shows bar graph comparing tumor weights between shControl and shSirt1 groups. Panel F shows organoid histology and immunostaining for indicated molecular markers. Panel G shows heatmap of relative neuroendocrine marker expression across experimental groups. Panel H shows schematic strategy for pharmacological inhibition of SIRT1 in organoids. Panel I shows heatmap of relative marker expression following Selisistat treatment concentrations.

SIRT1 silencing or pharmacological inhibition reverts NEPC. (A–G) Sirt1 silencing in a mouse organoid model of NEPC. (A) Schematic representation showing mouse NEPC organoids treated with shRNAs targeting Sirt1 and subjected to in vitro and in vivo analyses. (B) Shown are images of allografted tumors from the indicated groups imaged at the time of euthanasia (n = 6/group). (C) Representative images of allografted tumors grown from organoids (n = 6/group). Shown are H&E and immunostaining for AR, PanCK, Vimentin (Vim), Insm1, and synaptophysin (Syp). Scale bar = 50 μm. (D) Tumor volume measurements for the indicated groups. N = 6/group. P value was calculated using a two-way ANOVA test. (E) Bar plot with overlaid dots showing the tumor weight (g) for the indicated groups of mice (n = 6/group). P value was calculated using the Welch’s two sample t test. (F) Representative images of organoids from the indicated groups (n = 6/group). Shown are H&E and immunostaining for the indicated markers. Scale bar = 20 μm. (G) Heatmap representation of relative expression levels of the Sirt1, Ar, and the indicated markers of NEPC. (H and I) Pharmacological inhibition of Sirt1 in mouse NEPC organoids. (H) Schematic representation showing mouse NEPC organoids treated with the SIRT1 inhibitor Selisistat. (I) Heatmap representation of relative expression levels of Sirt1, Ar, and the indicated markers of NEPC for the indicated groups of organoids. Experiments were performed in quadruplicate and with a minimum of two independent biological replicates. See also Fig. S5.

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