MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages
MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages
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MNX 1-HNF 1B轴在乳腺导管内乳头状黏液性肿瘤中的表达
DOI：
10.1053/j.gastro.2021.12.254
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发表时间：
2022-03-15
期刊：
影响因子：
29.4
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Kato, Hiroyuki;Tateishi, Keisuke;Koike, Kazuhiko
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，其在癌症发展的多样性中的作用仍然未知。在胰腺癌中，胰腺导管腺癌（PDAC）和导管内乳头状粘液性肿瘤（IPMN）与相关的浸润性癌（IPMNinv）来自2种不同的前体，它们的根本差异仍然不清楚。在这里，我们的目的是评估染色质结构的差异调节转录签名或胰腺癌的生物学特征。方法：我们从胰腺肿瘤的不同亚型中建立了28个人类类器官，包括IPMN，IPMNinv和PDAC。我们进行了外显子组测序（seq），RNA-seq，转座酶可接近染色质-seq，染色质免疫沉淀-seq，高通量染色体构象捕获和表型分析与短发夹RNA或成簇的规律间隔的短回文重复干扰。结果：建立的类器官成功地再现了原发性肿瘤的组织学。IPMN和IPMNinv类器官含有GNAS、RNF 43或KLF 4突变，与PDAC相比显示出不同的表达谱。染色质可及性分布揭示了IPMN中胃特异性开放区域的获得和IPMNinv中不同胃肠道组织的模式。相反，与正常胰管相比，PDAC呈现出令人印象深刻的可接近区域的损失。转录因子足迹分析和功能测定表明，MNX 1和HNF 1B是IPMN谱系生物学上不可或缺的。MNX 1的上调在人IPMN谱系组织中特异性标记。MNX 1-HNF 1B轴控制着一组基因，包括MYC、SOX 9和OLFM 4，这些基因已知对胃肠道干细胞至关重要。高通量的染色体构象捕获分析表明，HNF 1B靶基因在IPMNinv基因组中是三维连接的。结论：我们的类器官分析确定MNX 1-HNF 1B轴在IPMN谱系中具有生物学意义。
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.