RBPJ deficiency sensitizes pancreatic acinar cells to Kras-mediated PanIN initiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA784421 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17062800_1.fastq.gz | Fastqsanger.gz | |||
| SRR17062800_2.fastq.gz | Fastqsanger.gz | |||
| SRR17062801_1.fastq.gz | Fastqsanger.gz | |||
| SRR17062801_2.fastq.gz | Fastqsanger.gz | |||
| SRR17062802_1.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is among the most common causes of cancer death worldwide. KrasG12D mutation is the main driver mutation but insuffi-cient for progression of invasive cancer on its own indicating that other pathways, such as Notch signaling may participate in that process. RBPJ, the only transcription factor in Notch signaling, is frequently lost in human cancers and associated with more aggressive breast cancer phenotype. Notch-independently, in complex with P48, RBPJ initiates transcription of its paralogue RBPJL ensuring acinar differentiation. The RBPJ knockout has an embryonic lethal effect. Mice with pancreas-specific deletion of RBPJ presented with less acinar tissue and large duct-like structures suggesting a relevance of RBPJ for acinar to ductal reprogramming and even pancreatic neoplasia. Here, we found reduced RBPJ expression level in the human PDAC specimens. Analyses of transgenic mouse models of an inducible P48-dependent RBPJ knockout revealed that it is dispensable for the maintenance adult acinar cells. In the context of oncogenic KRAS expression, the RBPJ deficiency facilitated the development of PanIN lesions with massive fibrotic stroma. Interestingly, RNA seq data revealed corresponding transcription pattern prior to phenotypic alterations.
2023-10-03 | GSE189756 | GEO
Project description:The goal of this study is to identify changes in gene expression between acinar and low-grade PanIN lesions in p48Cre;LSL-KrasG12D mice.
2024-11-11 | GSE280352 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is believed to arise from the accumulation of a series of somatic mutations and is also frequently associated with pancreatic intraepithelial neoplasia (PanIN) lesions. However, there is still debate as to whether the cell-type-of-origin of PanINs and PDACs is acinar or ductal. As cell type identity is maintained epigenetically, DNA methylation changes during pancreatic neoplasia can provide a compelling perspective to examine this question, but DNA methylation sequencing has not yet been performed genome-wide on purified exocrine and neoplastic cell types in the pancreas. Thus, we performed genome-wide DNA methylation sequencing on acini, non-neoplastic ducts, PanIN lesions, and PDAC lesions. We found that: 1) both global methylation profiles and block DMRs clearly implicate an acinar origin for PanINs; 2) at the gene level, PanIN lesions exhibit an intermediate acinar-ductal phenotype resembling acinar-to-ductal metaplasia (ADM); and 3) PanINs are epigenetically primed to progress to PDAC. Thus, epigenomic analysis complements histopathology to define molecular progression toward PDAC.
2023-05-08 | GSE222147 | GEO
Project description:Background and aimsDevelopment of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary. Here, we focused on RBPJ, the receiving transcription factor in the Notch pathway, examined its expression pattern in PDAC, and characterized its function in mouse models of pancreatic cancer development and in the regeneration process after acute pancreatitis.MethodsConditional transgenic mouse models were used for functional analysis of RBPJ in the adult pancreas, initiation of PDAC precursor lesions, and pancreatic regeneration. Pancreata and primary acinar cells were tested for acinar-to-ductal metaplasia together with immunohistology and comprehensive transcriptional profiling by RNA sequencing.ResultsWe identified reduced RBPJ expression in a subset of human PDAC specimens. Ptf1α-CreERT-driven depletion of RBPJ in transgenic mice revealed that its function is dispensable for the homeostasis and maintenance of adult acinar cells. However, primary RBPJ-deficient acinar cells underwent acinar-to-ductal differentiation in ex vivo. Importantly, oncogenic KRAS expression in the context of RBPJ deficiency facilitated the development of pancreatic intraepithelial neoplasia lesions with massive fibrotic stroma formation. Interestingly, RNA-sequencing data revealed a transcriptional profile associated with the cytokine/chemokine and extracellular matrix changes. In addition, lack of RBPJ delays the course of acute pancreatitis and critically impairs it in the context of KRASG12D expression.ConclusionsOur findings imply that downregulation of RBPJ in PDAC patients derepresses Notch targets and promotes KRAS-mediated pancreatic acinar cells transformation and desmoplasia development.
| S-EPMC10520364 | biostudies-literature
Project description:p48Cre LSL-KrasG12D Mouse Acinar and PanIN LCM RNA-Seq
| PRJNA1177900 | ENA
Project description:Brahma related gene 1 (BRG1), a catalytic ATPase subunit of SWI/SNF chromatin remodeling complexes, is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDA). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and IPMN-derived PDA from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia (PanIN) from acinar cells remains elusive. Here, we investigated the role of BRG1 in PanIN initiation and maintenance and its underlying mechanisms. Exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1f/f (KBC) mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independent of the presence of p53 mutation. We found that Sox9 expression was down-regulated in both Brg1-depleted acinar cell explants and BRG1-depleted ADMs/PanINs. Sox9 overexpression rescued this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1-deletion in established PanIN by using an inducible dual recombinase system resulted in regression of the lesions in mice. Finally, expression of BRG1 and SOX9 was also positively correlated in human PanIN-derived PDAs. In summary, BRG1 is critical for both initiation and maintenance of PanIN. Mechanistically, this is mediated through positive regulation of SOX9 expression. Thus, the BRG1/SOX9 axis is a potential target for the prevention of PanIN-derived PDA.
2018-01-01 | GSE93615 | GEO
Project description:Mutations in members of the SWI/SNF chromatin remodeling family are common events in human cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the pancreas of mice in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.
2018-07-03 | GSE114567 | GEO
Project description:Mutations in members of the SWI/SNF chromatin remodeling family are common events in human cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the pancreas of mice in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.
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Project description:Cellular senescence is a central barrier to tumorigenesis, acting to block the proliferation of premalignant cells. However, senescent cells residing within tumor lesions can also exert paracrine effects influencing tumor growth and progression. Premalignant pancreatic intraepithelial neoplasia (PanIN) lesions contain senescent cells, yet whether these influence disease progression is unknown. Here we report that senescent cells in PanINs that develop in a Kras-driven mouse model express a pro-inflammatory gene signature, which includes high Cox2 levels. Pharmacologic Cox2 inhibition caused a dramatic reduction in PanIN growth. Senolytic treatment with the Bcl2-family inhibitor ABT-737 reduced the numbers of Cox2-expressing PanIN cells and blocked PanIN formation and progression to carcinoma. These findings indicate that senescent PanIN cells support tumor growth and progression through Cox2 activity, representing crosstalk between interspersed senescent and dividing premalignant cells. Targeted elimination of senescent cells may thus be effective in limiting progression of precancerous lesions.
2021-02-17 | GSE128319 | GEO
Project description:The rising incidence of pancreatic cancer is largely driven by the skyrocketing prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of both conditions, and is independently associated with increased cancer incidence and mortality. Our previous studies demonstrated that genetically reducing insulin production suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, we found that hyperinsulinemia affected many cell types in the pancreatic microenvironment. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment, and molecular mechanisms involved were unknown. Here, we tested whether insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are necessary for the effects of hyperinsulinemia on obesity-associated pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not prevent hyperinsulinemia or weight gain associated with high fat diet (HFD) consumption in mice. However, solely reducing Insr in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors, in a gene dose-dependent manner. Mechanistically, proteomic analyses showed that hyperinsulinemia acts through Insr to drive the excess production of digestive enzymes in acinar cells by modulating the activity of the spliceosome, ribosome, and secretory machinery. This resulted in increased inflammation, which was abrogated by acinar-specific Insr knockout. We confirmed that insulin increased the conversion of wild-type acinar cells into acinar-to-ductal metaplasia (ADM) in a trypsin-dependent manner. Collectively, these data demonstrate that hyperinsulinemia acting via acinar cells insulin receptors promotes inflammatory conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer, mechanistically linking obesity and pancreatic cancer.
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