FIGURE 1.

Uro A treatment downregulates PI3K/AKT/mTOR pathway, reduces primary tumor burden, alters the stromal composition and immunomodulatory profile of the TME in a spontaneous murine model of PDAC. A, mRNA levels of AKT1 in normal pancreatic tissue (Normal; n = 171) and patients with primary PDAC (Tumor; n = 179) from GTEx and pancreatic adenocarcinoma (PAAD) TCGA database. B, Representative H&E-stained pancreas sections and IHC imaging analysis demonstrating pAKT and pP70S6K expression in the pancreatic tissue sections of non–tumor-bearing Ptf1a^Cre, and tumor-bearing KPC and PKT GEMMs of PDAC. Quantification of relative areas of positive staining in (within the tumor area) tissue sections from vehicle, and Uro A-treated tumors are indicated in adjacent plots. C, Schematic of vehicle or Uro A (20 mg/kg/day) treatment in PKT mice. Treatment was initiated at 4.5 weeks of age when mice reproducibly developed palpable tumors and was continued for 3 weeks before sacrifice. D, Pancreas weight analysis of Uro A or vehicle-treated PKT mice. E, Western blot analysis showing decreased pAKT and pP70S6K in PKT mice pancreata after Uro A treatment as compared with vehicle-treated PKT mice, n = 3 mice/group. F, Representative H&E-stained tumor sections, and IHC imaging analysis demonstrating reduction in pAKT and pP70S6K expression within the ductal compartment of pancreatic tissue sections following Uro A treatment in PKT GEMM, n = 3 mice/group. G, Collagen 1, trichrome blue staining, and their corresponding quantification analysis in pancreatic tumor tissues harvested from PKT mice treated with Uro A or vehicle, n = 5 mice/group. H, Cytokine array profiling of pancreatic tumor tissues harvested from PKT mice treated with Uro A or vehicle. Scale bar = 50 μm. Individual datapoints with mean ± SEM are shown and compared by two-tailed unpaired t test for two group comparison and one-way ANOVA for multiple comparisons; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ^ns, P > 0.05.