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

Abstract

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.

The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression?

“…Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the Western world ( 57 ). Recent integrated multiplatform sequencing analyses of PDAC have revealed ARID1A mutations in 6% of the cases ( 58 , 59 ). ARID1A may function as a tumor-suppressor gene in pancreatic carcinogenesis, because its expression levels are associated with tumor differentiation and tumor stage, but not to lymph node metastasis, distant metastasis, sex, or age ( 60 ).…”

“…ARID1A may function as a tumor-suppressor gene in pancreatic carcinogenesis, because its expression levels are associated with tumor differentiation and tumor stage, but not to lymph node metastasis, distant metastasis, sex, or age ( 60 ). In a pancreas-specific mutant Arid1a -driven mouse model ( Ptf1a-Cre;Kras G12D ;Arid1a f/f ), despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), deficiency of Arid1a in mice pancreas develops aggressive PDAC in later ages with extensive parenchymal replacement by mucinous cysts resembling low-grade branched duct gastric type IPMN (LG-IPMN) in humans ( 59 , 61 ), suggesting Arid1a loss accelerates PDAC formation.…”

Vaginal squamous cell carcinoma develops in mice withArid1aloss and gain of oncogenicKras

“…However, even with long-term (60 day) 17b-estradiol treatment, endometrial cancer was not discovered, suggesting that something molecular may be restraining cancer in the endometrium rather than the vagina. Similarly, in the pancreatic cancer field, oncogenic Kras was found to be insufficient to drive pancreatic adenocarcinoma due to the protective effects of ARID1A [42][43][44][45][46][47]. For example, oncogenic expression of Kras G12D alone leads to pancreatic intraepithelial lesions but not malignancy.…”

“…These studies all support the hypothesis that ARID1A restrains malignant transformation from benign lesions driven by oncogenic Kras G12D . Work in pancreatic adenocarcinoma [42][43][44][45][46][47] has identified escape mechanisms that need to be explored in the endometrium.…”

Interplay of ARID1A and EGFR signaling in controlling acinar cell reprogramming in the pancreas

“…While the functional implications of Arid1a deficiency in Kras-driven pancreatic carcinogenesis have been studied intensively, findings characterizing the consequences of sole Arid1a deficiency in the absence of oncogenic Kras are conflicting (Wang S.C et al 2019;Livshits et al 2018;Ferri-Borgogno et al 2019). We propose, that Arid1a deficiency critically impacts on acinar reprogramming and hypothesize that the chromatin remodeling protein´s function and activity is critically influenced by the activity of signaling pathways which also play a pivotal role in acinar cell plasticity and pancreatic carcinogenesis.…”