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ABSTRACT

BACKGROUND AND AIMS Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from two distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating transcriptional signatures or biological features in pancreatic cancers. METHODS We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome-seq, RNA-seq, ATAC-seq, ChIP-seq, Hi-C, and phenotypic analyses with shRNA or CRISPR interference. RESULTS Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared to PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions in comparison with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. Hi-C analysis suggested the HNF1B target genes to be three-dimensionally connected in the genome of IPMNinv. CONCLUSION Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.

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