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

Hiroyuki Kato; Keisuke Tateishi; Hiroaki Fujiwara; Takuma 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; Tomotaka Saito; Naminatsu Takahara; Takahiro Kishikawa; Tsuyoshi Hamada; Ryota Takahashi; Koji Miyabayashi; Suguru Mizuno; Hirofumi Kogure; Yousuke Nakai; Yoshihiro Hirata; Atsushi Toyoda; Kazuki Ichikawa; Wei Qu; Shinichi Morishita; Junichi Arita; Mariko Tanaka; Tetsuo Ushiku; Kiyoshi Hasegawa; Mitsuhiro Fujishiro; Kazuhiko Koike

doi:10.1053/j.gastro.2021.12.254

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

Hiroyuki Kato, Keisuke Tateishi, Hiroaki Fujiwara, Takuma 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 SaitoTomotaka Saito, Naminatsu Takahara, Takahiro Kishikawa, Tsuyoshi Hamada, Ryota Takahashi, Koji Miyabayashi, Suguru Mizuno, Hirofumi Kogure, Yousuke Nakai, Yoshihiro Hirata, Atsushi Toyoda, Kazuki Ichikawa, Wei Qu, Shinichi Morishita, Junichi Arita, Mariko Tanaka, Tetsuo Ushiku, Kiyoshi Hasegawa, Mitsuhiro Fujishiro, Kazuhiko Koike

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1272-1287.e16
Journal	Gastroenterology
Volume	162
Issue number	4
DOIs	https://doi.org/10.1053/j.gastro.2021.12.254
Publication status	Published - Apr 2022
Externally published	Yes

Keywords

Chromatin Structure
Epigenetics
HNF1B
Intraductal Papillary Mucinous Neoplasm
MNX1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1053/j.gastro.2021.12.254

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Kato, H., Tateishi, K., Fujiwara, H., Nakatsuka, T., Yamamoto, K., Kudo, Y., Hayakawa, Y., Nakagawa, H., Tanaka, Y., Ijichi, H., Otsuka, M., Iwadate, D., Oyama, H., Kanai, S., Noguchi, K., Suzuki, T., Sato, T., Hakuta, R., Ishigaki, K., ... Koike, K. (2022). MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages. Gastroenterology, 162(4), 1272-1287.e16. https://doi.org/10.1053/j.gastro.2021.12.254

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title = "MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages",

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.",

keywords = "Chromatin Structure, Epigenetics, HNF1B, Intraductal Papillary Mucinous Neoplasm, MNX1",

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

note = "Publisher Copyright: {\textcopyright} 2022 AGA Institute",

year = "2022",

month = apr,

doi = "10.1053/j.gastro.2021.12.254",

language = "English",

volume = "162",

pages = "1272--1287.e16",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "4",

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Kato, H, Tateishi, K, Fujiwara, H, Nakatsuka, T, Yamamoto, K, Kudo, Y, Hayakawa, Y, Nakagawa, H, Tanaka, Y, Ijichi, H, Otsuka, M, Iwadate, D, Oyama, H, Kanai, S, Noguchi, K, Suzuki, T, Sato, T, Hakuta, R, Ishigaki, K, Saito, K, Saito, T, Takahara, N, Kishikawa, T, Hamada, T, Takahashi, R, Miyabayashi, K, Mizuno, S, Kogure, H, Nakai, Y, Hirata, Y, Toyoda, A, Ichikawa, K, Qu, W, Morishita, S, Arita, J, Tanaka, M, Ushiku, T, Hasegawa, K, Fujishiro, M & Koike, K 2022, 'MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages', Gastroenterology, vol. 162, no. 4, pp. 1272-1287.e16. https://doi.org/10.1053/j.gastro.2021.12.254

TY - JOUR

T1 - MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages

AU - Kato, Hiroyuki

AU - Tateishi, Keisuke

AU - Fujiwara, Hiroaki

AU - Nakatsuka, Takuma

AU - Yamamoto, Keisuke

AU - Kudo, Yotaro

AU - Hayakawa, Yoku

AU - Nakagawa, Hayato

AU - Tanaka, Yasuo

AU - Ijichi, Hideaki

AU - Otsuka, Motoyuki

AU - Iwadate, Dosuke

AU - Oyama, Hiroki

AU - Kanai, Sachiko

AU - Noguchi, Kensaku

AU - Suzuki, Tatsunori

AU - Sato, Tatsuya

AU - Hakuta, Ryunosuke

AU - Ishigaki, Kazunaga

AU - Saito, Kei

AU - Saito, Tomotaka

AU - Takahara, Naminatsu

AU - Kishikawa, Takahiro

AU - Hamada, Tsuyoshi

AU - Takahashi, Ryota

AU - Miyabayashi, Koji

AU - Mizuno, Suguru

AU - Kogure, Hirofumi

AU - Nakai, Yousuke

AU - Hirata, Yoshihiro

AU - Toyoda, Atsushi

AU - Ichikawa, Kazuki

AU - Qu, Wei

AU - Morishita, Shinichi

AU - Arita, Junichi

AU - Tanaka, Mariko

AU - Ushiku, Tetsuo

AU - Hasegawa, Kiyoshi

AU - Fujishiro, Mitsuhiro

AU - Koike, Kazuhiko

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - Chromatin Structure

KW - Epigenetics

KW - HNF1B

KW - Intraductal Papillary Mucinous Neoplasm

KW - MNX1

UR - http://www.scopus.com/inward/record.url?scp=85126320002&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2021.12.254

DO - 10.1053/j.gastro.2021.12.254

M3 - Article

C2 - 34953915

AN - SCOPUS:85126320002

SN - 0016-5085

VL - 162

SP - 1272-1287.e16

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

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