MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages

生物 导管内乳头状粘液性肿瘤 癌症研究 胰腺 HNF1B型 染色质免疫沉淀 ARID1A型 染色质 转录因子 胰腺癌 基因 遗传学 癌症 同源盒 基因表达 突变 发起人 生物化学
作者
Hiroyuki Kato,Keisuke Tateishi,Hiroaki Fujiwara,T. Nakatsuka,Keisuke Yamamoto,Yotaro Kudo,Yoku Hayakawa,Hayato Nakagawa,Yasuo Tanaka,Hideaki Ijichi,Motoyuki Otsuka,Dosuke Iwadate,Hiroki Oyama,Sachiko Kanai,Kensaku Noguchi,Tatsunori Suzuki,Tatsuya Sato,Ryunosuke Hakuta,Kazunaga Ishigaki,Kei Saito
出处
期刊:Gastroenterology [Elsevier BV]
卷期号:162 (4): 1272-1287.e16 被引量:21
标识
DOI:10.1053/j.gastro.2021.12.254
摘要

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 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers.We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference.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 with 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 compared 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. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv.Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.
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