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Project description:FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia
| PRJNA986430 | ENA
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:Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive.We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA) in the pancreatic acinar compartment.We observed that TβRICA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β, Sox9, and Hes1.We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients.
| S-EPMC5524227 | biostudies-other
Project description:Background and aimsAberrant acinar to ductal metaplasia (ADM), one of the earliest events involved in exocrine pancreatic cancer development, is typically studied using pancreata from genetically engineered mouse models.MethodsWe used primary, human pancreatic acinar cells from organ donors to evaluate the transcriptional and pathway profiles during the course of ADM.ResultsFollowing 6 days of three-dimensional culture on Matrigel, acinar cells underwent morphological and molecular changes indicative of ADM. mRNA from 14 donors' paired cells (day 0, acinar phenotype and day 6, ductal phenotype) was subjected to whole transcriptome sequencing. Acinar cell specific genes were significantly downregulated in the samples from the day 6 cultures while ductal cell-specific genes were upregulated. Several regulons of ADM were identified including transcription factors with reduced activity (PTF1A, RBPJL, and BHLHA15) and those ductal and progenitor transcription factors with increased activity (HNF1B, SOX11, and SOX4). Cells with the ductal phenotype contained higher expression of genes increased in pancreatic cancer while cells with an acinar phenotype had lower expression of cancer-associated genes.ConclusionOur findings support the relevancy of human in vitro models to study pancreas cancer pathogenesis and exocrine cell plasticity.
| S-EPMC10328139 | biostudies-literature
Project description:Tubular complexes (TCs) are aggregates of duct-like monolayered cells in the developing and regenerating pancreas. Recent studies showed that TCs have regenerative potential, including islet neogenesis. We previously delivered adenovirus vector (AdV) into exocrine cells of the pancreas by intra-common bile ductal (ICBD) injection, and found that AdV expressing Pdx1, a pancreas-specific transcription factor, causes TC formation and islet neogenesis. We also established RTF-Pdx1-EGFP mice, which ubiquitously express Pdx1 when tetracycline is removed from the drinking water. However, exogenous Pdx1 expression in adult RTF-Pdx1-EGFP mice did not cause any pathological changes in the pancreas during three weeks of observation after tetracycline withdrawal. To examine whether the host immune response induced by AdV was involved in TC formation, we delivered AdVs expressing pancreas-related transcription factors or an irrelevant protein into the pancreas of RTF-Pdx1-EGFP mice. Histological analyses showed that both AdV injection and Pdx1 expression are required for TC formation. We also analyzed the effects of these ICBD-injected AdVs. AdV expressing Isl1, a proendocrine transcription factor, effectively induced TC formation through acinar-to-ductal metaplasia, and exogenous Pdx1 expression facilitated this process. Considering the regenerative potential of TCs, a strategy that efficiently induces TC formation may lead to novel therapies for diabetes.
| S-EPMC3471997 | biostudies-literature
Project description:Pancreatic differentiation 2 (PD2), a PAF (RNA Polymerase II Associated Factor) complex subunit, is overexpressed in pancreatic cancer cells and has demonstrated potential oncogenic property. Here, we report that PD2/Paf1 expression was restricted to acinar cells in the normal murine pancreas, but its expression increased in the ductal cells of KrasG12D/Pdx1Cre (KC) mouse model of pancreatic cancer with increasing age, showing highest expression in neoplastic ductal cells of 50 weeks old mice. PD2/Paf1 was specifically expressed in amylase and CK19 double positive metaplastic ducts, representing intermediate structures during pancreatic acinar-to-ductal metaplasia (ADM). Similar PD2/Paf1 expression was observed in murine pancreas that exhibited ADM-like histology upon cerulein challenge. In normal mice, cerulein-mediated inflammation induced a decrease in PD2/Paf1 expression, which was later restored upon recovery of the pancreatic parenchyma. In KC mice, however, PD2/Paf1 mRNA level continued to decrease with progressive dysplasia and subsequent neoplastic transformation. Additionally, knockdown of PD2/Paf1 in pancreatic acinar cells resulted in the abrogation of Amylase, Elastase and Lipase (acinar marker) mRNA levels with simultaneous increase in CK19 and CAII (ductal marker) transcripts. In conclusion, our studies indicate loss of PD2/Paf1 expression during acinar transdifferentiation in pancreatic cancer initiation and PD2/Paf1 mediated regulation of lineage specific markers.
| S-EPMC4147339 | biostudies-literature
Project description:Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-?1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.
| S-EPMC4971483 | biostudies-literature
Project description:Pancreatic acinar cells display a remarkable degree of plasticity and can dedifferentiate into ductal-like progenitor cells by a process known as acinar ductal metaplasia (ADM). ADM is believed to be one of the earliest precursor lesions toward the development of pancreatic ductal adenocarcinoma and maintaining the pancreatic acinar cell phenotype suppresses tumor formation. The effects of a novel pStat3 inhibitor (LLL12B) and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) were investigated using 3-D cultures from p48Cre/+ and p48Cre/+LSL-KrasG12D/+ (KC) mice. LLL12B and TSA inhibited ADM in both KC and p48Cre/+ mouse pancreatic organoids. Furthermore, treatment with LLL12B or TSA on dedifferentiated acini from p48Cre/+ and KC mice that had undergone ADM produced morphologic and gene expression changes that suggest a reversal of ADM. Validation experiments using qRT-PCR (p48Cre/+ and KC) and RNA sequencing (KC) of the LLL12B and TSA treated cultures showed that the ADM reversal was more robust for the TSA treatments. Pathway analysis showed that TSA inhibited Spink1 and PI3K/AKT signaling during ADM reversal. The ability of TSA to reverse ADM was also observed in primary human acinar cultures. We report that pStat3 and HDAC inhibition can attenuate ADM in vitro and reverse ADM in the context of wild-type Kras. Our findings suggest that pharmacological inhibition or reversal of pancreatic ADM represents a potential therapeutic strategy for blocking aberrant ductal reprogramming of acinar cells.
| S-EPMC9440259 | biostudies-literature