Figure 7. Downregulation of p300/GATA6 led to pancreatic cancer subtype transition and Wnt independence.

(A) mRNA expression levels of pancreatic lineage, differentiation-related, epithelial, and classical subtype genes in orthotopic xenografts of HPAF-II NTC cells or EP300-knockout cells analyzed by RNA-Seq. Data are represented as mean and individual data points. Each dot represents an independent tumor. (B and C) EP300 or GATA6 knockout changed tissue morphology in HPAF-II tumors. Vehicle-treated tumors from Figure 4B and Figure 5E were subject to H&E staining. (B) The entire sections were scanned and the areas of regions with the defined tissue morphology were quantified. Tumors from 4 mice per group were analyzed. (C) Representative images of H&E staining results are shown. (D) EP300 or GATA6 knockout prevented upregulation of differentiation genes. TFF3 and AGR2 mRNA abundance was measured in control and ETC-159–treated subcutaneous HPAF-II xenografts (Figure 4B and Figure 5E). Three independent tumors per group were analyzed by RT-qPCR with technical replicates for each sample. P values of 2-tailed, unpaired t test between vehicle and ETC-159 treated samples are shown. (E) Schematic model of the p300/GATA6 differentiation axis whose deficiency bypasses Wnt dependency. Refer to the text for detailed description.