論文の公開元へLoss of Arid1a and Pten in Pancreatic Ductal Cells Induces Intraductal Tubulopapillary Neoplasm via the YAP/TAZ Pathway
概要
Gastroenterology 2022;163:466–480
Loss of Arid1a and Pten in Pancreatic Ductal Cells Induces
Intraductal Tubulopapillary Neoplasm via the YAP/TAZ Pathway
Yuichi Fukunaga,1,2,3 Akihisa Fukuda,1 Mayuki Omatsu,1 Mio Namikawa,1 Makoto Sono,1
Tomonori Masuda,1 Osamu Araki,1 Munemasa Nagao,1 Takaaki Yoshikawa,1 Satoshi Ogawa,1
Yukiko Hiramatsu,1 Yu Muta,1 Motoyuki Tsuda,1 Takahisa Maruno,1 Yuki Nakanishi,1
Jorge Ferrer,4 Tatsuaki Tsuruyama,5 Toshihiko Masui,6 Etsuro Hatano,6 and Hiroshi Seno1
1
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; 2Department
of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; 3DSP
Cancer Institute, Sumitomo Dainippon Pharma Co., Osaka, Japan; 4Centre for Genomic Regulation (CRG), The Barcelona
Institute of Science and Technology, Barcelona, Spain; 5Kyoto University Clinical Bio Resource Center, Kyoto, Japan; and
6
Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School
of Medicine, Kyoto, Japan
GI CANCER
See editorial on page 371.
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma
(PDAC) arises from several types of premalignant lesions,
including intraductal tubulopapillary neoplasm (ITPN); however, the molecular pathogenesis of ITPN remains unknown.
METHODS: We performed studies with Hnf1b-CreERT2; Ptenf/f;
Arid1af/f mice to investigate the consequence of genetic deletion of Arid1a in adult pancreatic ductal cells in the context of
oncogenic PI3K/Akt pathway activation. RESULTS: Simultaneous deletion of Arid1a and Pten in pancreatic ductal cells
resulted in the development of ITPN, which progressed to
PDAC, in mice. Simultaneous loss of Arid1a and Pten induced
dedifferentiation of pancreatic ductal cells and Yes-associated
protein 1/Transcriptional coactivator with PDZ-binding motif
(YAP/TAZ) pathway activation. Consistent with the mouse data,
TAZ expression was found elevated in human ITPNs and ITPNderived PDACs but not in human intraductal papillary
mucinous neoplasms, indicating that activation of the TAZ
pathway is a distinctive feature of ITPN. Furthermore, pharmacological inhibition of the YAP/TAZ pathway suppressed the
dedifferentiation of pancreatic ductal cells and development of
ITPN in Arid1a and Pten double-knockout mice. CONCLUSION:
Concurrent loss of Arid1a and Pten in adult pancreatic ductal
cells induced ITPN and ITPN-derived PDAC in mice through
aberrant activation of the YAP/TAZ pathway, and inhibition of
the YAP/TAZ pathway prevented the development of ITPN.
These findings provide novel insights into the pathogenesis of
ITPN-derived PDAC and highlight the YAP/TAZ pathway as a
potential therapeutic target.
Keywords: Pancreatic Cancer; SWI/SNF Complex; Mouse
Models; YAP/TAZ Pathway; ITPN.
Abbreviations used in this paper: ATAC-seq, assay for transposaseaccessible chromatin using sequencing; EMT, epithelial to mesenchymal
transition; GSEA, Gene Set Enrichment Analysis; IHC, immunohistochemistry; IPMN, intraductal pancreatic mucinous neoplasm; ITPN,
intraductal tubulopapillary neoplasm; pAkt, phosphorylated-Akt; PanIN,
pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma; PTEN, phosphatase and tensin homologue; qRT-PCR, quantitative reverse-transcriptase polymerase chain reaction; RNA-seq, RNA
sequencing; TAZ, Transcriptional coactivator with PDZ-binding motif; VP,
verteporfin; YAP, Yes-associated protein 1.
Most current article
© 2022 by the AGA Institute.
0016-5085/$36.00
https://doi.org/10.1053/j.gastro.2022.04.020
August 2022
ancreatic ductal adenocarcinoma (PDAC) is a lethal
disease with an extremely poor prognosis,1 and thus
early diagnosis and more effective therapies are urgently
needed to improve patient outcomes. To this end, a better
understanding of the molecular mechanisms underlying
PDAC development is crucial. PDAC is thought to arise from
premalignant lesions, including pancreatic intraepithelial
neoplasia (PanIN), intraductal pancreatic mucinous
neoplasm (IPMN), and intraductal tubulopapillary neoplasm
(ITPN). ITPN, a rare subset of epithelial neoplasms of the
pancreas representing approximately 3% of premalignant
pancreatic tumors and 0.9% of all pancreatic exocrine
neoplasms,2 is characterized by intraductal tubulopapillary
growth and cellular dysplasia, and has been recently defined
as a distinct entity in the World Health Organization classification based on its unique morphological and genomic
features.2–4 The morphological and histological features of
ITPNs that distinguish them from IPMNs include no
observable secreted mucin, cribriform structure, tubulopapillary growth, cuboidal cells with little cytoplasmic mucin,
uniform high-grade atypia, and no MUC2 and MUC5AC
expression.4 Most ITPNs grow in the main pancreatic duct
with upstream dilatation and mimic PDAC, and those
growing only in branch ducts are extremely rare.
Recent sequencing studies have revealed that activating
mutations in KRAS are common in human PanINs5 and
PDACs6 and are often observed in IPMNs7,8; however, these
mutations are rarely found in patients with ITPN.2,9
Approximately 30% of ITPNs have activating mutations in
genes involved in the PI3K/Akt pathway (PIK3CA, PIK3CB,
INPP4A, PTEN) and chromatin-remodeling factors (MLL1,
MLL2, MLL3, BAP1, PBRM1, EED, and ATRX), suggesting that
ITPN harbors distinct genetic alterations.9 However, the
molecular mechanisms underlying ITPN and ITPN-derived
PDAC development are largely unknown, and genetically
engineered mouse models of ITPN and ITPN-derived PDAC
have not yet been established.
Recent genome-wide sequencing studies have shown
that mutations in subunit genes of the SWI/SNF chromatinremodeling complexes are widespread across diverse human cancers10,11 and have been found in 12% to 23% of
human PDACs.6,10,12 SWI/SNF complexes remodel the
chromatin structure using energy from ATP hydrolysis to
modulate gene expression.13 ARID1A is the most frequently
mutated subunit in SWI/SNF complexes in human PDAC,14
and decreased ARID1A protein expression is found in
various types of cancers, including PDAC.15–17 ARID1A plays
a role in the specific recruitment of the SWI/SNF complex by
binding to transcription factors.18 Using a mouse model, we
recently showed that loss of Arid1a in pancreatic ductal
cells synergistically acts with oncogenic Kras to induce
dedifferentiation of pancreatic ductal cells and IPMN
development, which subsequently develops into invasive
PDAC.19 Furthermore, another study showed that loss of
Arid1a in the context of oncogenic Kras led to the development of IPMN as well as the activation of epithelial to
mesenchymal transition (EMT) and stem cell transcriptional
programs in Arid1a-deficient murine PDAC cells.20
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WHAT YOU NEED TO KNOW
BACKGROUND AND CONTEXT
Intraductal tubulopapillary neoplasm has unique mutation
features, including no KRAS mutation and frequent
mutation in chromatin-remodeling factors and the PI3K/
AKT pathway; however, the molecular mechanism of
intraductal tubulopapillary neoplasm development is
largely unknown.
NEW FINDINGS
Simultaneous loss of ARID1A and phosphatase and
tensin homologue in pancreatic ductal cells induces
development of intraductal tubulopapillary neoplasm
through dedifferentiation and aberrant activation of the
Yes-associated protein 1/Transcriptional coactivator
with PDZ-binding motif (YAP/TAZ) pathway, and
pharmacological inhibition of the YAP/TAZ pathway
suppresses
intraductal
tubulopapillary
neoplasm
formation in mice.
LIMITATIONS
Further studies are required to elucidate the molecular
mechanism of aberrant activation of the YAP/TAZ
pathway in ARID1A- and PTEN-mutated pancreatic
ductal cells.
IMPACT
Aberrant activation of the YAP/TAZ pathway is a
molecular feature of intraductal tubulopapillary neoplasm
and
intraductal
tubulopapillary
neoplasm–derived
pancreatic ductal adenocarcinomas, and inhibition of
the YAP/TAZ pathway could be a novel therapeutic
approach for intraductal tubulopapillary neoplasm and
intraductal tubulopapillary neoplasm–derived pancreatic
ductal adenocarcinomas.
Recent studies have reported a high co-occurrence of
ARID1A with PTEN or PIK3CA mutations in several types of
cancer, including ovarian clear cell carcinoma, uterine
endometrioid carcinoma, and uterine serous carcinoma.21,22
These findings suggest a synergistic effect between the loss
of Arid1a and activation of the PI3K/Akt pathway on
oncogenesis. However, the in vivo role of ARID1A in
pancreatic tumorigenesis in the context of oncogenic activation of the PI3K/Akt pathway remains unknown.
Therefore, in this study, we aimed to investigate the
impact of Arid1a inactivation in pancreatic ductal cells in the
context of oncogenic PI3K/Akt pathway activation and
clarify the functional role of Arid1a in the specification and
development of PDAC and its precursors in mice.
Materials and Methods
Mice
Experimental animals were generated by crossing Hnf1bCreERT2 mice (a gift from Jorge Ferrer, Imperial College, London, UK),23 Arid1aflox mice,24 and Ptenflox mice (Stock no.
004597; The Jackson Laboratory, Bar Harbor, ME). The mice
were crossed with a mixed background. For the induction of
Cre-mediated recombination, tamoxifen (Sigma-Aldrich, St
Louis, MO) was administered a total of 3 times: once a day by
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Loss of Arid1a and Pten Induces ITPN in Mice
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Fukunaga et al
oral gavage at a dose of 400 mg/kg, every 2 days. Pancreatic
tissue from Ptf1a-Cre; KrasG12D; Arid1aflox/flox mice were prepared as described previously.19 All experiments involving
mice were approved by the animal research committee of
Kyoto University (Kyoto, Japan) and performed in accordance
with Japanese government regulations. ...
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