Fig. 1: Aberrant SNAIL expression dramatically accelerates KRAS^G12D-driven PDAC formation.

a Genetic strategy to activate SNAIL and KRAS^G12D expression in the pancreas. b Immunoblot analysis of SNAIL protein expression in pancreas of 1-month-old Ptf1a^Cre/+;LSL-Kras^G12D/+ (PKras^G12D/+) and Ptf1a^Cre/+;LSL-Kras^G12D/+;LSL-R26^Snail/+ (PKras^G12D/+;Snail^KI/+) compound mutant mice. c Representative hematoxylin and eosin (H&E), Alcian blue (AB), Muc5a, CK19 and BrdU stains of acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) in 1-month-old PKras^G12D/+ and PKras^G12D/+;Snail^KI/+ mice. Note the almost complete remodelling of pancreatic tissue in PKras^G12D/+;Snail^KI/+ animals. Scale bars, 50 μm. d Quantification of ADM and PanIN progression in % of total lesions at age of one-month (error bars, mean ± SEM; n = 4 per genotype; 3 representative slides per mouse; *p = 0.037, Mann-Whitney two-tailed test). e Quantification of ductal and acinar structures after in vitro culture of acinar explants for 5 days (n = 3 control/PKras^G12D/+ mice, n = 5 PKras^G12D/+;Snail^KI/+ mice; mean ± SEM; *p = 0.036, Mann-Whitney two-tailed test). f Gene-set enrichment analysis (GSEA) using mRNA expression profiles of PKras^G12D/+;Snail^KI/+ (red) and PKras^G12D/+ (blue) pancreata of 1-month-old mice (n = 2 per genotype) computed and corrected for multiple testing using the Benjamini–Hochberg procedure (for statistical details, please see methods section). Genes were ranked using Signal-to-Noise ratio statistics according to their correlation. Vertical black lines mark the position of each gene in the data set. Normalized Enrichment Score: 3.15; Nominal p-value < 0.0001; False Discovery Rate (FDR) q-value < 0.0001. g Kaplan-Meier survival curves of PKras^G12D/+ (n = 125; 465 days median survival), PKras^G12D/+;Snail^KI/+ (n = 42; 190 days median survival) and PKras^G12D/+;Snail^KI/KI (n = 28; 64 days median survival) mice (***p < 0.0001, log-rank test, Bonferroni correction). h Macroscopic view and representative H&E and BrdU staining of pancreata with PDAC of three endpoint mice per genotype (tu tumour; st stomach; sp spleen). Scale bars, 50 µm. Note: The PKras^G12D/+ cohort in (g) is the same shown in Figs. 4b, 6e, f and the PKras^G12D/+;Snail^KI/+ cohort is the same shown in Figs. 6e, l. Source data of Fig. 1 are provided in the Source Data file.