Fig. 1: 14-3-3ζ-induced Yap1 activation in PDAC cells and Cox2 in fibroblasts confer adaptive Gem resistance that is inhibited by co-targeting Yap1 and Cox2. | Cell Discovery

Fig. 1: 14-3-3ζ-induced Yap1 activation in PDAC cells and Cox2 in fibroblasts confer adaptive Gem resistance that is inhibited by co-targeting Yap1 and Cox2.

From: Targeting a chemo-induced adaptive signaling circuit confers therapeutic vulnerabilities in pancreatic cancer

Fig. 1

a Kaplan–Meier survival analysis of patients with 14-3-3ζ-high (n = 114) and -low expressing (n = 12) PDACs (log-rank test). b Kaplan–Meier survival analysis of KPC (n = 10) and KPC-ζfl/fl (n = 9) mice treated with Gem (Log-Rank test). c Relative cell number of PANC-1.shCtrl/shζ cells 3D-cultured in the lower chambers of a Transwell unit with or without 3D-cultured hPSCs in the upper chambers of a Transwell unit treated with Gem (20 nM) for 72 h (mean ± SD, t-test, n = 3 biological repeats). d Gene set enrichment analysis (GSEA) of Yap1 signature in 14-3-3ζ-high vs 14-3-3ζ-low human PDACs in the TCGA dataset. e Western blotting (WB) analyses of cytoplasmic and nuclear Yap1, 14-3-3ζ, tubulin (a cytoplasmic protein marker, sample processing controls), and YY1 (a nuclear protein marker, sample processing controls) in 3D-cultured PACN-1.shCtrl vs PACN-1.shζ cells that were treated with Gem (20 nM) or vehicle for 3 h. Representative data of two independent repeats. f RPPA analysis of NIH3T3 cells treated with CM collected from Panc02 cells cultured in 10% or 0% FBS medium. g WB analysis of Cox2 and GAPDH (sample processing controls) in NIH3T3 cells treated with CM from Panc02.shCtrl or shζ cells treated with or without Gem (20 nM, 72 h). Representative data of two independent repeats. h Relative cell number of Panc02 cells under indicated modifications and conditions; Panc02-GFP cells and NIH3T3 cells were transfected with control or indicated siRNAs respectively, then co-cultured and treated with Gem (8.5 nM) or vehicle. Panc02:NIH3T3 = 1:9 (mean ± SD, t-test, n = 3 biological repeats). i Schematics of in vivo experiment in Fig. 1j, k. Panc02.shCtrl ind. are Panc02.doxy-inducible shCtrl cells, Panc02.shYap1 ind. are Panc02.doxy-inducible shYap1 cells. j IHC staining of Yap1 in PDACs from intrapancreatic injection of Panc02.doxy-inducible shCtrl and Panc02.doxy-inducible shYap1 cells. scale bar: 25 µm. k Left: Quantification of tumor volumes of doxy-treated mice bearing Panc02.doxy-inducible shCtrl or Panc02.doxy-inducible shYap1 tumors 1 week after the indicated treatments (mean, Mann–Whitney test). Right: Images of treated Panc02 tumors.

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