Figure 3 from PPARδ Orchestrates a Prometastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer

<p><i>PPARD</i> expression is linked to metabolic switch and EMT in patients with PDAC. <b>A,</b> Expression levels of <i>PPARD</i> in PDAC tumors (T) vs. surrounding normal tissue (N) included in the TCGA and GTEx projects. <b>B,</b> Patients were dichotomized for <i>PPARD</i> expression [higher (<i>n</i> = 58) and lower (<i>n</i> = 81) expression compared with the mean; RNA-seq V2 RSEM values]. Kaplan–Meier curves for disease-free survival are shown. Dotted lines denote the confidence intervals. Survival, 19.48 vs. 13.53 months. <b>C</b> and <b>D,</b> A TMA with 108 cases was stained by IHQ using an anti–PPARδ antibody. Representative images depicting different signal intensities (weak vs. strong) and localizations (nuclear vs. cytoplasmatic) are shown in <b>C</b>. Magnification, ×400. Scale bar, 50 μm. Arrows, stained cancer cells. <b>D,</b> Signal intensity was scored by Allred immunoreactive score, and patients were dichotomized into low (<i>n</i> = 34; scores 0–6) vs. high (<i>n</i> = 59; scores 7–8) PPARδ expression groups. Kaplan–Meier curves for overall survival are shown. Dotted lines denote the confidence intervals. Survival, 17.5 vs. 11 months. <b>E,</b> Correlation between <i>PPARD</i> tumor expression levels family members and an EMT-associated signature composed of <i>SNAI1</i>, <i>SNAI2</i>, and <i>ZEB1</i>. <b>F,</b> Gene sets enriched in the transcriptional profile of tumors belonging to the top <i>PPARD</i> high-expression group compared with the bottom low-expression group in the TCGA data series (PAAD, pancreatic adenocarcinoma). Shown are the normalized enrichment score (NES) values for each pathway using the Hallmark gene sets, meeting the significance criteria: nominal <i>P</i> value of < 0.05, FDR < 25%. <b>G,</b> Enrichment plot for TNFα, EMT, glycolysis, and hypoxia hallmarks in <i>PPARD</i>-high vs. -low samples shown in <b>F</b>, indicating values of normalized enrichment score and FDR <i>q</i> values. <b>H,</b> Representative images of costaining of PPARδ (nuclear and cytoplasmatic, red) and HIF1α (nuclear brown) by IHQ in several patients shown in <b>C</b> and <b>D</b>. Magnification, ×400. Scale bar, 50 μm. Arrows, costained cancer cells. See also Supplementary Fig. S6.</p>