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Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [snATAC]

ABSTRACT: Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [snATAC]

PROVIDER: PRJNA986435 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24988725_1.fastq.gz	Fastqsanger.gz
	SRR24988725_2.fastq.gz	Fastqsanger.gz
	SRR24988726_1.fastq.gz	Fastqsanger.gz
	SRR24988726_2.fastq.gz	Fastqsanger.gz
	SRR24988727_1.fastq.gz	Fastqsanger.gz

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Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [snATAC]

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

Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [RNA-seq]

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Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [CUT&RUN]

2024-06-09 | GSE235540 | GEO

FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia

Project description:FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia

| PRJNA986430 | ENA

mTORC1 and mTORC2 converge on the Arp2/3 complex to promote KrasG12D-induced acinar-to-ductal metaplasia and early pancreatic carcinogenesis

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

Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [CUT&RUN]

Project description:Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [CUT&RUN]

| PRJNA986434 | ENA

Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [RNA-seq]

Project description:Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [RNA-seq]

| PRJNA986436 | ENA

RNA-Seq of explanted murine pancreatic acinar cells from wt, KrasG12D, Pi3kCAH1047R and Mek1dd mice

Project description:To investigate the underlying changes during acinar-to-ductal metaplasia induced by different factos, pancreatic acinar cells were isolated from 5 week old wt, KrasG12D, Pi3kCAH1047R and Mek1dd mice. Acinar cells from wt mice were treated with medium (control), Tgfa or IL17a. RNA was isolated immediately after isolation (t=0 days) or after 2-3 days embedded in collagen.

2024-05-31 | E-MTAB-11913 | biostudies-arrayexpress

RNA-Seq of explanted murine pancreatic acinar cells

Project description:To investigate the underlying changes during acinar-to-ductal metaplasia, pancreatic acinar cells were isolated from 5 week old KrasG12D-mice. RNA was isolated immediately after isolation (t=0 days) or after 3 days embedded in collagen.

2023-03-02 | E-MTAB-9878 | biostudies-arrayexpress

Transcriptional Profile Of Human Pancreatic Acinar Ductal Metaplasia

Project description:Aberrant acinar to ductal metaplasia (ADM), one of the earliest events involved in exocrine pancreatic cancer development, is typically studied using pancreata from transgenic mouse models. We used primary, human pancreatic acinar cells to evaluate the transcriptional profile during the course of ADM.

2022-06-01 | GSE179248 | GEO

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