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Cell of origin can change the transcriptome profile of tumors arising from distinct pancreatic cell types Zarei, Soheila

Abstract

Both acinar and ductal cells can give rise to PDAC in murine models. However, the gene expression profiles of these tumors, as well as their role in tumor heterogeneity remain unknown. The objective of this study was to understand whether the cellular origin of PDAC could cause functional or molecular heterogeneity. We created PDAC cell lines from mouse models (Sox9CreER;KrasLSL-G12D;Trp53f/f mice a.k.a. Duct:Kras-p53 mice and Ptf1aCreER;KrasLSL-G12D;Trp53f/f a.k.a. Acinar:Kras-p53 mice), which developed tumors originating from ductal or acinar cells, respectively. Duct:Kras-p53 mice formed high grade PanINs, developed PDAC much faster, and had a shorter lifespan compared to Acinar:Kras-p53 mice. In contrast, Acinar:Kras-p53 mice formed abundant of low grade PanINs with mucinous characteristics and PDAC initiation was delayed. I performed differential gene expression analysis between 12 acinar- and 13 ductal-cell-derived tumors using a specific R programming language package called DESeq2. I found 827 differentially expressed genes between tumors of different cellular origin (p-value < 0.05). Of these differentially expressed genes 260 genes were upregulated in ductal-cell-derived PDAC and 567 genes were upregulated in acinar-cell-derived PDAC. The gene enrichment analysis suggests that GO ontology categories “Glycoproteins pathways” and “stomach” were enriched in the transcripts upregulated in acinar-cell-derived tumors only. Keratin 20 (CK20), a marker of mucinous differentiation in the gut, is one of the top 20 differentially expressed genes (log2 fold change=6.1) with enriched expression in acinar-cell-derived tumors. Quantification of the total CK20 and Alcian Blue positive area of tumors indicates that CK20 and the gastric mucinous-gland phenotype indicated by Alcian Blue are positively associated. Other than CK20, components of the Wnt/beta-catenin signaling pathways, including Wnt5a, Wnt10a and Wnt4, were differentially expressed between ductal- and acinar-cell-derived PDAC cell lines. Using an inhibitor of Wnt/beta-catenin signaling pathways, ICG-001, I found that beta-catenin inhibition limited both ductal- and acinar-cell-derived PDAC cell proliferation. This was accompanied by decreased expression of Birc5 and increased Cdkn1a expression, which are suggested to be targets of beta-catenin. Overall, I have shown that cell of origin can have subtle effects on the transcriptome of PDAC and begun to characterize the functional profiles of PDAC of different cellular origins.

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