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Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis

Ferri-Borgogno, Sammy and Barui, Sugata and McGee, Amberly M. and Griffiths, Tamara and Singh, Pankaj K. and Piett, Cortt G. and Ghosh, Bidyut and Bhattacharyya, Sanchari and Singhi, Aatur and Pradhan, Kith and Verma, Amit and Nagel, Zac and Maitra, Anirban and Gupta, Sonal (2020) Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis. Cancers, 12 (9). p. 2695. ISSN 2072-6694

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Background & Aims: ARID1A 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 and PDAC cell lines. Methods: Pancreas-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 human and murine PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cell 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. Results: Retention of Arid1a 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 various compensatory (“escaper”) mechanisms to overcome the growth suppressive effects of Arid1a loss. Conclusions: Arid1a 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. In tumors that arise in the setting of ARID1A loss, a multitude of “escaper” mechanisms drive progression.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Ferri-Borgogno, Sammy
Barui, Sugata
McGee, Amberly M.
Griffiths, Tamara
Singh, Pankaj K.
Piett, Cortt G.
Ghosh, Bidyut
Bhattacharyya, Sanchari
Singhi, Aaturads130@pitt.eduads1300000-0003-3930-7096
Pradhan, Kith
Verma, Amit
Nagel, Zac
Maitra, Anirban
Gupta, Sonal
Date: 21 September 2020
Date Type: Publication
Journal or Publication Title: Cancers
Volume: 12
Number: 9
Publisher: MDPI AG
Page Range: p. 2695
DOI or Unique Handle: 10.3390/cancers12092695
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Uncontrolled Keywords: SWI/SNF, pancreatic cancer, DNA repair, mouse model
ISSN: 2072-6694
Official URL:
Funders: National Institutes of Health, Pancreatic Cancer Moon Shot program of UT MD Anderson Cancer Center
Article Type: Research Article
Date Deposited: 04 Jun 2021 17:25
Last Modified: 04 Jun 2021 17:25


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