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• W4281718394 abstract "See “Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway,” by Fukunaga Y, Fukuda A, Omatsu M, et al, on page 466. Pancreatic intraepithelial neoplasia, intraductal pancreatic mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN) are the common precursor lesions of pancreatic cancer. The gene abnormalities of those precursor lesions are characterized by Kras mutation and mucin overexpression.1Caldas C. Hahn S.A. Hruban R.H. et al.Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia.Cancer Res. 1994; 54: 3568-3573PubMed Google Scholar,2Omori Y. Ono Y. Tanino M. et al.Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features.Gastroenterology. 2019; 156: 647-661.e2Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Arid1a is a subunit of the SWI/SNF complex, which serves as a tumor suppressor gene commonly absent in subsets of pancreatic cancer and IPMN patients, and low expression of Arid1a is associated with poor overall survival of pancreatic cancer.3Liu S. Cao W. Niu Y. et al.Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence.Elife. 2021; 10e64204Google Scholar,4Wang S.C. Nassour I. Xiao S. et al.SWI/SNF component ARID1A restrains pancreatic neoplasia formation.Gut. 2019; 68: 1259-1270Crossref PubMed Scopus (38) Google Scholar Kimura et al5Kimura Y. Fukuda A. Ogawa S. et al.ARID1A maintains differentiation of pancreatic ductal cells and inhibits development of pancreatic ductal adenocarcinoma in mice.Gastroenterology. 2018; 155: 194-209.e2Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar showed that deletion of Arid1a in the pancreas of mice induced pancreatic cancer when synergized with Kras activation. Arid1a is also essential for IPMN formation. Wang et al4Wang S.C. Nassour I. Xiao S. et al.SWI/SNF component ARID1A restrains pancreatic neoplasia formation.Gut. 2019; 68: 1259-1270Crossref PubMed Scopus (38) Google Scholar,6Wang W. Friedland S.C. Guo B. et al.ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas.Gut. 2019; 68: 1245-1258Crossref PubMed Scopus (40) Google Scholar showed that loss of Arid1a in combination with Kras activation accelerated IPMN formation in mice. It is suggested that loss of Arid1a leads to IPMN formation and pancreatic cancer through the Sox9 and mammalian target of rapamycin (mTOR) pathways and that the level of Arid1a may determine the response of patients with pancreatic cancer to mTOR inhibitor treatment.5Kimura Y. Fukuda A. Ogawa S. et al.ARID1A maintains differentiation of pancreatic ductal cells and inhibits development of pancreatic ductal adenocarcinoma in mice.Gastroenterology. 2018; 155: 194-209.e2Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar However, the underlying mechanism by which Arid1a is lost in pancreatic cancer and IPMN is unclear and must be further investigated. Other than pancreatic intraepithelial neoplasia and IPMN, the World Health Organization recognized in 2010 a new subtype of precursor lesions, called intraductal tubulopapillary neoplasm (ITPN).7Urata T. Naito Y. Nagamine M. et al.Intraductal tubulopapillary neoplasm of the pancreas with somatic BRAF mutation.Clin J Gastroenterol. 2012; 5: 413-420Crossref PubMed Scopus (15) Google Scholar ITPN is a rare precursor lesion that is distinguished from IPMN due to high-grade nuclear atypia, tubule formation, dilated duct, and absence of mucin production.8Assarzadegan N. Babanianmansour S. Shi J. Updates in the diagnosis of intraductal neoplasms of the pancreas.Front Physiol. 2022; 13856803Google Scholar ITPN often shows positive staining of ductal cell markers CK7 and CK19, but negative staining of mucin biomarkers MUC2 and MUC5AC.9Kim H. Ro J.Y. Intraductal tubulopapillary neoplasm of the pancreas: an overview.Arch Pathol Lab Med. 2018; 142: 420-423Crossref PubMed Scopus (6) Google Scholar In 2021, based on whole-exome sequencing, Gross et al10Gross C. Engleitner T. Lange S. et al.Whole exome sequencing of biliary tubulopapillary neoplasms reveals common mutations in chromatin remodeling genes.Cancers (Basel). 2021; 13: 2742Crossref PubMed Scopus (6) Google Scholar demonstrated the absence of KRAS, rare TP53, and SMAD4 mutation in patients with ITPN. ITPN has unique genetic characteristics, including chromatin remodeling and phosphoinositide 3-kinase pathway mutations.10Gross C. Engleitner T. Lange S. et al.Whole exome sequencing of biliary tubulopapillary neoplasms reveals common mutations in chromatin remodeling genes.Cancers (Basel). 2021; 13: 2742Crossref PubMed Scopus (6) Google Scholar,11Basturk O. Berger M.F. Yamaguchi H. et al.Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma.Mod Pathol. 2017; 30: 1760-1772Crossref PubMed Scopus (46) Google Scholar Owing to the rarity of this precursor lesion, the molecular mechanism and gene profiles are still unclear. In this issue of Gastroenterology, Fukunaga et al12Fukunaga Y. Fukuda A. Omatsu M. et al.Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway.Gastroenterology. 2022; 163: 466-480Abstract Full Text Full Text PDF Scopus (1) Google Scholar identified a novel function of Arid1a in ITPN that has not been investigated in this disease before. Previous studies have shown that loss of Arid1a synergized with activation of the phosphoinositide 3-kinase/Akt pathway led to many types of cancer.13Caumanns J.J. Berns K. Wisman G.B.A. et al.Integrative kinome profiling identifies mTORC1/2 inhibition as treatment strategy in ovarian clear cell carcinoma.Clin Cancer Res. 2018; 24: 3928-3940Crossref PubMed Scopus (24) Google Scholar,14Mullen J. Kato S. Sicklick J.K. et al.Targeting ARID1A mutations in cancer.Cancer Treat Rev. 2021; 100102287Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Fukunaga’s group is the first to establish the spontaneous transgenic mouse model with Arid1a and Pten deleted in the pancreatic ductal cells to investigate the synergized role of Arid1a and Pten in vivo. In the transgenic HPA (Hnf1b-CreERT2; Ptenf/f; Arid1af/f) mice, the histologic changes, including tubular structure, dilated duct, and oval-shaped nuclei, recapitulated the classical characteristics of human ITPN. Consistent with previous findings, positive MUC1 staining and negative MUC2 and MUC5AC staining was also identified in the mice. However, the researchers observed that inactivation of Arid1a or Pten alone was not sufficient for ITPN development.12Fukunaga Y. Fukuda A. Omatsu M. et al.Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway.Gastroenterology. 2022; 163: 466-480Abstract Full Text Full Text PDF Scopus (1) Google Scholar How Arid1a and Pten synergistically drive ITPN development is not known. Yes-associated protein (YAP) is one of the major effectors of the Hippo pathway during cell differentiation and tissue development.15Gruber R. Panayiotou R. Nye E. et al.YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling.Gastroenterology. 2016; 151: 526-539Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar YAP is a transcriptional coactivator binding to TEAD/TAZ to form a complex and drives target gene transcription.16Liu M. Zhang Y. Yang J. et al.Zinc-dependent regulation of ZEB1 and YAP1 coactivation promotes epithelial-mesenchymal transition plasticity and metastasis in pancreatic cancer.Gastroenterology. 2021; 160: 1771-1783.e1Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar YAP1 and TAZ are required for acinar-to-ductal metaplasia induced by Kras, and activation of YAP1 and TAZ in the acinar cells is sufficient to stimulate pancreatic cancer in vivo.15Gruber R. Panayiotou R. Nye E. et al.YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling.Gastroenterology. 2016; 151: 526-539Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar However, ITPN is originated from ductal cells, and whether YAP/TAZ-TEAD is required for ductal cell development is unclear. Fukunaga et al12Fukunaga Y. Fukuda A. Omatsu M. et al.Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway.Gastroenterology. 2022; 163: 466-480Abstract Full Text Full Text PDF Scopus (1) Google Scholar found that the YAP/TAZ activity was activated in HPA mice, but not in HA (Hnf1b-CreERT2; Arid1af/f) or HP (Hnf1b-CreERT2; Ptenf/f) mice. Next, they found that Arid1a impaired the interactions between the SWI/SNF complex and YAP/TAZ to activate the YAP/TAZ-TEAD pathway.12Fukunaga Y. Fukuda A. Omatsu M. et al.Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway.Gastroenterology. 2022; 163: 466-480Abstract Full Text Full Text PDF Scopus (1) Google Scholar However, the mechanism by which Arid1a and Pten collaborated to activate YAP/TAZ-TEAD is still unclear. Wilson et al17Wilson M.R. Reske J.J. Holladay J. et al.ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion.Nat Commun. 2019; 10: 3554Crossref PubMed Scopus (66) Google Scholar elucidated that blocking of Arid1a increased F-actin expression, suggesting that loss of Arid1a transmitted the F-actin into the nucleus and generated the high mechanical state to activate YAP by mechanical force.18McClatchey A.I. Georgopoulos K. Actin’ up to stop SNFin out TEAD.Dev Cell. 2018; 47: 693-695Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Chang et al19Chang L. Azzolin L. Di Biagio D. et al.The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ.Nature. 2018; 563: 265-269Crossref PubMed Scopus (149) Google Scholar identified that under low mechanical stress, the Hippo pathway is turned on and Arid1a interacts with the WW domain of YAP through the PPXY motif to form an Arid1a-SWI/SNF-YAP/TAZ complex, which separates YAP/TAZ and TEAD. When Arid1a is deleted, YAP/TAZ is released from the Arid1a-SWI/SNF complex and forms a complex with TEAD to restore the YAP/TAZ-TEAD interaction and activate the downstream gene targets.19Chang L. Azzolin L. Di Biagio D. et al.The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ.Nature. 2018; 563: 265-269Crossref PubMed Scopus (149) Google Scholar However, under low mechanical environment, only loss of Pten cannot fully restore YAP/TAZ activity in the absence of Arid1a concomitant inactivation, which may suggest an explanation for why ITPN was induced in the transgenic mice in which Arid1a and Pten were deleted synergistically. Therefore, multiple factors are required to activate YAP/TAZ to induce ITPN. Since ITPN and IPMN both arise from pancreatic ductal cells, the researchers also investigated the YAP/TAZ-TEAD pathway in the PKA mice and observed that the YAP/TAZ-TEAD pathway was not activated, although IPMN developed.12Fukunaga Y. Fukuda A. Omatsu M. et al.Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway.Gastroenterology. 2022; 163: 466-480Abstract Full Text Full Text PDF Scopus (1) Google Scholar When mice were treated with YAP inhibitor VP, no ITPN was formed in HPA mice. It is suggested that YAP/TAZ activity is important for ITPN formation and that the downstream targets of YAP/TAZ, such as connective tissue growth factor, Ankrd1, and Birc5, are essential for ITPN development but are dispensable for IPMN formation. The target gene signatures of YAP/TAZ-TEAD in ITPN must be studied further. Deficiency of Arid1a is essential for precursor lesions formation and pancreatic cancer development (Figure 1). Loss of Arid1a synergized with Kras mutation led to IPMN, but deficiency of Arid1a and Pten increased cellular mechanical stress to activate YAP/TAZ and drove ITPN formation. Hippo signaling, mechanical force, and SWI/SNF sequestration are suggested to be essential components for YAP/TAZ activity stimulation. Fukunaga et al12Fukunaga Y. Fukuda A. Omatsu M. et al.Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway.Gastroenterology. 2022; 163: 466-480Abstract Full Text Full Text PDF Scopus (1) Google Scholar identified the new function of Arid1a in ITPN and elucidated a novel signaling pathway of Arid1a/Pten-YAP/TAZ/TEAD. This study shed light on underlining the dependency and distinct role of YAP/TAZ on the mechanical responsiveness of ITPN to the physical environment. However, the molecular mechanisms by which Arid1a is deficient in the precursor lesions and the gene signatures of YAP/TAZ signaling are involved in ITPN must be further investigated. Loss of Arid1a and Pten in Pancreatic Ductal Cells Induces Intraductal Tubulopapillary Neoplasm via the YAP/TAZ PathwayGastroenterologyVol. 163Issue 2PreviewSimultaneous loss of Arid1a and Pten in pancreatic ductal cells induces development of intraductal tubulopapillary neoplasm and pancreatic ductal adenocarcinoma through activation of the YAP/TAZ pathway in mice, and pharmacological inhibition of the YAP/TAZ pathway suppresses formation of intraductal tubulopapillary neoplasm. Full-Text PDF" @default.
• W4281718394 created "2022-06-13" @default.
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• W4281718394 date "2022-08-01" @default.
• W4281718394 modified "2023-09-29" @default.
• W4281718394 title "Arid1a: A Gatekeeper in the Development of Pancreatic Cancer From a Rare Precursor Lesion" @default.
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