ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice

Kimura, Yukinobu; Fukuda, Akira; Ogawa, Satoshi; Maruno, Takahisa; Takada, Y; Tsuda, Motoyuki; Hiramatsu, Yukiko; Araki, Osamu; Nagao, Munemasa; Yoshikawa, Takaaki; Ikuta, Kozo; Yoshioka, Taiyo; Zong, Wang; Akiyama, Haruhiko; Wright, Christopher V.E.; Takaori, Kyoichi; Üemoto, Shinji; Chiba, Tsutomu; Seno, Hiroshi

doi:10.1053/j.gastro.2018.03.039

Cited by 66 publications

(105 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with previous reports,7 Arid1a depletion alters the type of precursor lesions that precede PDAC formation and gives rise to intraductal papillary mucinous neoplastic lesions instead of the typical pancreatic intraepithelial neoplastic lesions observed in the majority of transgenic PDAC models. This alternative preneoplastic route towards PDAC has been previously described for pancreatic tumours deficient of the SWI/SNF family member SMARCA4 (coding for BRG1),8 and hence seems to be a characteristic phenomenon for genetic alterations of this chromatin remodelling complex in the pancreas.…”

supporting

confidence: 92%

Chromatin remodelling controls pancreatic tissue fate

Heßmann¹,

Ellenrieder²

2019

Gut

View full text Add to dashboard Cite

supporting

confidence: 92%

Chromatin remodelling controls pancreatic tissue fate

Heßmann¹,

Ellenrieder²

2019

Gut

View full text Add to dashboard Cite

“…Notably, these findings are in sharp contrast to well established TSGs, like TRP53 and CDKN2A, which demonstrate a progressive increase in rate of alterations from low grade to high grade precursors to invasive adenocarcinoma 11 , and where the frequency of mutations is typically higher in neoplasms at the aggressive end of the spectrum versus indolent tumors. These lines of evidence suggest that loss of Arid1a might not demonstrate outright genetic cooperation with oncogenic Ras in the pancreatic epithelium and thus warrant a careful reappraisal of the TSG role for ARID1A during multistep neoplastic progression ascribed in recently published GEM models [5][6][7][8] .…”

Section: Discussionmentioning

confidence: 99%

“…These predicted loss-of-function alterations has led to the prevailing assumption that ARID1A behaves as a classic tumor suppressor gene (TSG), likely demonstrating genetic cooperation with mutant KRAS in pancreatic tumorigenesis. In fact, several recent genetically engineered mouse (GEM) models have been developed, largely based on this premise, with the investigators generating mice with pancreas-specific Arid1a loss and mutant Kras expression [5][6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

“…Predominantly, these GEM models showed appearance of intraductal papillary mucinous neoplasms (IPMNs), a bona fide precursor lesion of PDAC, with only one study reporting progression to PDAC on the backdrop of IPMNs in 20% of these mice. This led the investigators to conclude that loss of Arid1a in the context of mutant Kras results in an IPMN -PDAC pathway to invasive cancer in the pancreas 5 . However, rather inexplicably, other studies have also shown that the rate of ARID1A mutation or loss of expression in human IPMN samples is substantially higher than in human PDAC samples 5,7,9,10 .…”

Section: Introductionmentioning

confidence: 99%

“…This led the investigators to conclude that loss of Arid1a in the context of mutant Kras results in an IPMN -PDAC pathway to invasive cancer in the pancreas 5 . However, rather inexplicably, other studies have also shown that the rate of ARID1A mutation or loss of expression in human IPMN samples is substantially higher than in human PDAC samples 5,7,9,10 . This stands in stark contrast to all of the wellestablished TSGs in PDAC (particularly TP53, SMAD4 and CDKN2A), which consistently demonstrate an increasing frequency of abnormalities in the multistep progression from precursors to invasive cancer 4,11 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis

Ferri-Borgogno

Barui

McGee

et al. 2019

Preprint

View full text Add to dashboard Cite

Background & AimsARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model, PDAC cell lines.MethodsPancreas-specific mutant Arid1a-driven GEM model (Ptf1a-Cre;KrasG12D;Arid1af/f or “KAC”) was generated by crossing Ptf1a-Cre;KrasG12D (“KC”) mice with Arid1af/f mice and characterized histologically with timed necropsies. Arid1a was also deleted using CRISPR-Cas9 system in established PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cells lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay.ResultsArid1a is critical for early progression of mutant Kras-driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in “KAC” as compared to “KC” mice. Enforced deletion of Arid1a in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of “KAC” mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous “KAC” mice revealed epigenetic changes underlying the various compensatory mechanisms to overcome the growth suppressive effects of Arid1a loss.ConclusionsArid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models.

show abstract

Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Zhao

Li²,

Wang

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

Background Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by the untargetable non‐G12C KRAS mutations, and only a small subset of patients are eligible for FDA‐approved precision therapies. The practice of precision therapy in pancreatic cancer was limited by the paucity of targetable genetic alterations, especially in the Asian population. Methods To explore therapeutic targets in 499 Chinese PDAC patients, a deep sequencing panel (OncoPanscan™, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants. Results We performed genomic profiling in 499 Chinese PDAC patients, which revealed somatic driver mutations in KRAS, TP53, CDKN2A, SMAD4, ARID1A, RNF43, and pathogenic germline variants (PGVs) in cancer predisposition genes including BRCA2, PALB2, and ATM. Overall, 20.4% of patients had targetable genomic alterations. About 8.4% of patients carried inactivating germline and somatic variants in BRCA1/2 and PALB2, which were susceptible to platinum and PARP inhibitors therapy. Patients with KRAS wild‐type disease and early‐onset pancreatic cancer (EOPC) harbored actionable mutations including BRAF, EGFR, ERBB2, and MAP2K1/2. Compared to PGV‐negative patients, PGV‐positive patients were younger and more likely to have a family history of cancer. Furthermore, PGVs in PALB2, BRCA2, and ATM were associated with high PDAC risk in the Chinese population. Conclusions Our results demonstrated that a genetic screen of actionable genomic variants could facilitate precision therapy and cancer risk reduction in pancreatic cancer patients of Asian ethnicity.

show abstract

ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice

Abstract: ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.

Cited by 66 publications

References 54 publications

Chromatin remodelling controls pancreatic tissue fate

Chromatin remodelling controls pancreatic tissue fate

Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis

Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Contact Info

Product

Resources

About