<br>MNX1-HNF1B 轴对于导管内乳头状粘液性肿瘤谱系是不可或缺的,Gastroenterology

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MNX1-HNF1B 轴对于导管内乳头状粘液性肿瘤谱系是不可或缺的
Gastroenterology ( IF 25.7 ) Pub Date : 2021-12-22 , DOI: 10.1053/j.gastro.2021.12.254
Hiroyuki Kato ₁ , Keisuke Tateishi ₁ , Hiroaki Fujiwara ₂ , Takuma Nakatsuka ₁ , Keisuke Yamamoto ₁ , Yotaro Kudo ₁ , Yoku Hayakawa ₁ , Hayato Nakagawa ₁ , Yasuo Tanaka ₁ , Hideaki Ijichi ₁ , Motoyuki Otsuka ₁ , Dosuke Iwadate ₁ , Hiroki Oyama ₁ , Sachiko Kanai ₁ , Kensaku Noguchi ₁ , Tatsunori Suzuki ₁ , Tatsuya Sato ₁ , Ryunosuke Hakuta ₁ , Kazunaga Ishigaki ₁ , Kei Saito ₁ , Tomotaka Saito ₁ , Naminatsu Takahara ₁ , Takahiro Kishikawa ₁ , Tsuyoshi Hamada ₁ , Ryota Takahashi ₁ , Koji Miyabayashi ₁ , Suguru Mizuno ₁ , Hirofumi Kogure ₁ , Yousuke Nakai ₃ , Yoshihiro Hirata ₄ , Atsushi Toyoda ₅ , Kazuki Ichikawa ₆ , Wei Qu ₆ , Shinichi Morishita ₆ , Junichi Arita ₇ , Mariko Tanaka ₈ , Tetsuo Ushiku ₈ , Kiyoshi Hasegawa ₇ , Mitsuhiro Fujishiro ₁ , Kazuhiko Koike ₁

Affiliation

背景与目标

染色质结构通过调节特定基因表达来控制细胞谱系；然而，它在癌症发展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) 伴相关浸润性癌 (IPMNinv) 由两种不同的癌前病变产生，它们的根本区别仍然不清楚。在这里，我们的目的是评估调节胰腺癌转录特征或生物学特征的染色质结构的差异。

方法

我们从不同的胰腺肿瘤亚型中建立了 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、转座酶可及染色质-seq 测定、染色质免疫沉淀-seq、高通量染色体构象捕获，以及使用短发夹 RNA 或成簇规则间隔短回文重复干扰的表型分析。

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 、 RNF43或KLF4突变，并与 PDAC 相比显示出不同的表达谱。染色质可及性图谱揭示了 IPMN 中胃特异性开放区域的增加以及 IPMNinv 中不同胃肠组织的模式。相比之下，与正常胰管相比，PDAC 的可及区域明显减少。转录因子足迹分析和功能测定表明，MNX1 和 HNF1B 对于 IPMN 谱系在生物学上是不可或缺的。 MNX1 的上调在人类 IPMN 谱系组织中特别明显。 MNX1-HNF1B 轴控制一组基因，包括MYC 、 SOX9和OLFM4 ，已知这些基因对于胃肠道干细胞至关重要。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 3 维连接。

结论

我们的类器官分析发现 MNX1-HNF1B 轴在 IPMN 谱系中具有生物学意义。

"点击查看英文标题和摘要"

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

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.