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MNX1-HNF1B轴对于导管内乳头状黏液性肿瘤谱系至关重要。

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

作者信息

Kato Hiroyuki, Tateishi Keisuke, Fujiwara Hiroaki, Nakatsuka Takuma, Yamamoto Keisuke, Kudo Yotaro, Hayakawa Yoku, Nakagawa Hayato, Tanaka Yasuo, Ijichi Hideaki, Otsuka Motoyuki, Iwadate Dosuke, Oyama Hiroki, Kanai Sachiko, Noguchi Kensaku, Suzuki Tatsunori, Sato Tatsuya, Hakuta Ryunosuke, Ishigaki Kazunaga, Saito Kei, Saito Tomotaka, Takahara Naminatsu, Kishikawa Takahiro, Hamada Tsuyoshi, Takahashi Ryota, Miyabayashi Koji, Mizuno Suguru, Kogure Hirofumi, Nakai Yousuke, Hirata Yoshihiro, Toyoda Atsushi, Ichikawa Kazuki, Qu Wei, Morishita Shinichi, Arita Junichi, Tanaka Mariko, Ushiku Tetsuo, Hasegawa Kiyoshi, Fujishiro Mitsuhiro, Koike Kazuhiko

机构信息

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

出版信息

Gastroenterology. 2022 Apr;162(4):1272-1287.e16. doi: 10.1053/j.gastro.2021.12.254. Epub 2021 Dec 22.

DOI:10.1053/j.gastro.2021.12.254

PMID:34953915

Abstract

BACKGROUND & 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 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.

METHODS

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.

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 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.

CONCLUSIONS

Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.

摘要

背景与目的

染色质结构通过调节特定基因表达来控制细胞谱系；然而，其在癌症发展多样性中的作用仍不清楚。在胰腺癌中，胰腺导管腺癌（PDAC）和伴有浸润性癌的导管内乳头状黏液性肿瘤（IPMNinv）起源于两种不同的前体，它们的根本差异仍不清楚。在此，我们旨在评估调节胰腺癌转录特征或生物学特性的染色质结构差异。

方法

我们从胰腺肿瘤的不同亚型中建立了28种人类类器官，包括IPMN、IPMNinv和PDAC。我们进行了外显子组测序（seq）、RNA测序、转座酶可及染色质测序分析、染色质免疫沉淀测序、高通量染色体构象捕获，以及使用短发夹RNA或成簇规律间隔短回文重复序列干扰进行表型分析。

结果

建立的类器官成功再现了原发性肿瘤的组织学特征。IPMN和IPMNinv类器官存在GNAS、RNF43或KLF4突变，与PDAC相比表现出不同的表达谱。染色质可及性图谱显示IPMN中胃特异性开放区域增加，IPMNinv中呈现多种胃肠道组织的模式。相比之下，与正常胰腺导管相比，PDAC的可及区域显著减少。转录因子足迹分析和功能测定确定MNX1和HNF1B对IPMN谱系在生物学上是不可或缺的。MNX1的上调在人类IPMN谱系组织中具有特异性标记。MNX1 - HNF1B轴调控一组基因，包括已知对胃肠道干细胞至关重要的MYC、SOX9和OLFM4。高通量染色体构象捕获分析表明HNF1B靶基因在IPMNinv基因组中呈三维连接。