P48Cre;LSL-KrasG12D Mouse Acinar and PanIN LCM RNA-Seq
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE280352 | GEO | 2024/11/11
REPOSITORIES: GEO
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Project description:p48Cre LSL-KrasG12D Mouse Acinar and PanIN LCM RNA-Seq
| PRJNA1177900 | ENA
Project description:To investigate the role of SHP2 (Ptpn11) in pancreatic carcinogenesis, murine pancreatic whole tissue RNA samples of 9 week old mice with the genotypes Ptf1a-Cre;LSL-KrasG12D (ID-labels Kxxx) and Ptf1a-Cre;LSL-KrasG12D;Ptpn11fl/fl (ID-labels Mxxxx) were analyzed by microarray.
2018-03-30 | E-MTAB-6399 | biostudies-arrayexpress
Project description:Acinar cells have been proposed as a cell-of-origin for pancreatic intraepithelial neoplasia (PanIN) after undergoing a highly regulated acinar to ductal metaplasia (ADM) process. ADM can be triggered by pancreatitis causing acinar cells de-differentiate to a ductal-like state. We identify Fra1 (gene name Fosl1) as the most enriched transcription factor during KrasG12D acute pancreatitis mediated injury. We have elucidated the functional role of Fra1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D (Ptf1aCreERT;KrasG12D;Fosl1fl/fl;YFP) . Using single nuclei ATAC-seq and bulk-RNA seq, we used pseudotime analysis and developed a gene-regulatory network governing de-differentiation to demonstrate that Fosl1 knockout mice are delayed in the onset of ADM and accompanying recovery. Fosl1 depletion prevents the pro-inflammatory effects of G-CSF, an ADM-promoting cytokine, suggesting that the G-CSF/Fra1 signaling axis can modulate ADM. Overall, our studies mark the first time a discrete transcriptional factor has been linked to the temporal regulation of ADM.
2024-06-09 | GSE235542 | GEO
Project description:Acinar cells have been proposed as a cell-of-origin for pancreatic intraepithelial neoplasia (PanIN) after undergoing a highly regulated acinar to ductal metaplasia (ADM) process. ADM can be triggered by pancreatitis causing acinar cells de-differentiate to a ductal-like state. We identify Fra1 (gene name Fosl1) as the most enriched transcription factor during KrasG12D acute pancreatitis mediated injury. We have elucidated the functional role of Fra1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D (Ptf1aCreERT;KrasG12D;Fosl1fl/fl;YFP) . Using single nuclei ATAC-seq and bulk-RNA seq, we used pseudotime analysis and developed a gene-regulatory network governing de-differentiation to demonstrate that Fosl1 knockout mice are delayed in the onset of ADM and accompanying recovery. Fosl1 depletion prevents the pro-inflammatory effects of G-CSF, an ADM-promoting cytokine, suggesting that the G-CSF/Fra1 signaling axis can modulate ADM. Overall, our studies mark the first time a discrete transcriptional factor has been linked to the temporal regulation of ADM.
2024-06-09 | GSE235541 | GEO
Project description:Acinar cells have been proposed as a cell-of-origin for pancreatic intraepithelial neoplasia (PanIN) after undergoing a highly regulated acinar to ductal metaplasia (ADM) process. ADM can be triggered by pancreatitis causing acinar cells de-differentiate to a ductal-like state. We identify Fra1 (gene name Fosl1) as the most enriched transcription factor during KrasG12D acute pancreatitis mediated injury. We have elucidated the functional role of Fra1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D (Ptf1aCreERT;KrasG12D;Fosl1fl/fl;YFP) . Using single nuclei ATAC-seq and bulk-RNA seq, we used pseudotime analysis and developed a gene-regulatory network governing de-differentiation to demonstrate that Fosl1 knockout mice are delayed in the onset of ADM and accompanying recovery. Fosl1 depletion prevents the pro-inflammatory effects of G-CSF, an ADM-promoting cytokine, suggesting that the G-CSF/Fra1 signaling axis can modulate ADM. Overall, our studies mark the first time a discrete transcriptional factor has been linked to the temporal regulation of ADM.
2024-06-09 | GSE235540 | GEO
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:Oncogenic KrasG12D, a driver mutation of pancreatic ductal adenocarcinoma (PDAC), induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). Here, we show that both functional complexes of mTOR (mechanistic target of rapamycin kinase, mTORC1 and mTORC2) are specifically activated in ADM. Murine models uncover that mTORC1 and mTORC2 cooperate to promote KrasG12D-driven ADM development. Proteomic analyses identify Arp2/3 complex, an actin nucleator, as the common downstream effector: mTORC1 is responsible for the protein synthesis of Rac1 and Arp3 while mTORC2 promotes the Arp2/3 complex activity via Akt/Rac1 signalling. Genetic ablation of Arp2/3 complex completely arrests KrasG12D-driven ADM development. The Arp2/3 complex-mediated y-branching of actin network promotes the basolateral spread of filamentous actin, which is indispensable for acinar cells-initiated carcinogenesis. Induced by oncogenic KrasG12D, ADM is a metaplastic phenotype of acinar cells that requires extensive actin rearrangements. mTORC1 and mTORC2, downstream targets of KrasG12D, have well-established oncogenic functions in PDAC development. The actin-related protein 2/3 (Arp2/3) complex is the first identified actin nucleator. Regarded as textbook knowledge, it is activated by EGFR/Rac1 signalling to promote the polymerisation of branched actin filaments from pre-existing filaments in numerous biological contexts. Hereby, we identify that mTORC1 and mTORC2 attain a dual, yet non-redundant, regulatory role in promoting Arp2/3 complex function, which is responsible for generating basolateral filamentous actin in ADM. Thus, the role of Arp2/3 complex fills up the missing gap between putative oncogenic signals and actin dynamics underlying PDAC initiation.
2021-01-07 | PXD018296 | Pride
Project description:Phosphoproteomic analysis to elucidate whether high-fat diet induced hyperinsulinemia contributes to pancreatic cancer directly through insulin receptor (INSR) signaling in KrasG12D-expressing pancreatic acinar cells.
2023-10-19 | PXD033845 | Pride
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: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