Comprehensive sequence-based DNA methylation analysis suggests that PanIN lesions are acinar-derived and epigenetically primed for carcinogenesis
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ABSTRACT:
PROVIDER: PRJNA918374 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22972400_1.fastq.gz | Fastqsanger.gz | |||
| SRR22972400_2.fastq.gz | Fastqsanger.gz | |||
| SRR22972401_1.fastq.gz | Fastqsanger.gz | |||
| SRR22972401_2.fastq.gz | Fastqsanger.gz | |||
| SRR22972402_1.fastq.gz | Fastqsanger.gz |
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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:The goal of this study is to identify changes in gene expression between acinar and low-grade PanIN lesions in p48Cre;LSL-KrasG12D mice.
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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:p48Cre LSL-KrasG12D Mouse Acinar and PanIN LCM RNA-Seq
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Project description:RBPJ deficiency sensitizes pancreatic acinar cells to Kras-mediated PanIN initiation
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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:This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing (scRNA-seq) integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. Our semi-supervised analysis pipeline was applied to examine pancreatic intraepithelial neoplasias (PanIN), the most frequent premalignant lesions that can develop into pancreatic adenocarcinoma (PDAC). Their strict diagnosis on FFPE samples has limited previous characterization of human PanINs within their microenvironment through single-cell approaches. We leverage unbiased whole transcriptome FFPE spatial profiling to enable this characterization in a rare cohort of matched low-grade and high-grade PanIN lesions to track progression and map cellular phenotypes relative to scRNA-seq data of advanced PDAC tumors. We demonstrate that cancer associated fibroblasts (CAF), including antigen-presenting CAFs (apCAF), are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We use these findings to guide panel design to perform single-cell validation with high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our pipeline for spatial multi-omics characterization provides a resource for future PanIN studies. Moreover, our semi-supervised learning framework to spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis.
2024-02-06 | GSE254829 | 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 in humans 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. Here, we performed laser-capture microdissection on surgically resected specimens from 18 patients to isolate, with high purity, DNA for whole-genome bisulfite sequencing from four relevant cell types: acini, nonneoplastic ducts, PanIN lesions, and PDAC lesions. Differentially methylated regions (DMR) were identified using two complementary analytical approaches: bsseq, which identifies any DMRs but is particularly useful for large block-like DMRs, and informME, which profiles the potential energy landscape across the genome and is particularly useful for identifying differential methylation entropy. Both global methylation profiles and block DMRs clearly implicated an acinar origin for PanINs. At the gene level, PanIN lesions exhibited an intermediate acinar-ductal phenotype resembling acinar-to-ductal metaplasia. In 97.6% of PanIN-specific DMRs, PanIN lesions had an intermediate methylation level between normal and PDAC, which suggests from an information theory perspective that PanIN lesions are epigenetically primed to progress to PDAC. Thus, epigenomic analysis complements histopathology to define molecular progression toward PDAC. The shared epigenetic lineage between PanIN and PDAC lesions could provide an opportunity for prevention by targeting aberrantly methylated progression-related genes.SignificanceAnalysis of DNA methylation landscapes provides insights into the cell-of-origin of PanIN lesions, clarifies the role of PanIN lesions as metaplastic precursors to human PDAC, and suggests potential targets for chemoprevention.
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Project description:This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing (scRNA-seq) integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. Our semi-supervised analysis pipeline was applied to examine pancreatic intraepithelial neoplasias (PanIN), the most frequent premalignant lesions that can develop into pancreatic adenocarcinoma (PDAC). Their strict diagnosis on FFPE samples has limited previous characterization of human PanINs within their microenvironment through single-cell approaches. We leverage unbiased whole transcriptome FFPE spatial profiling to enable this characterization in a rare cohort of matched low-grade and high-grade PanIN lesions to track progression and map cellular phenotypes relative to scRNA-seq data of advanced PDAC tumors. We demonstrate that cancer associated fibroblasts (CAF), including antigen-presenting CAFs (apCAF), are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We use these findings to guide panel design to perform single-cell validation with high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our pipeline for spatial multi-omics characterization provides a resource for future PanIN studies. Moreover, our semi-supervised learning framework to spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis.
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Project description:Epigenetic profile of tissues is reprogrammed under diseased conditions. H3K4Me3 and H3K27Me3 represent active and repressive epigenetic marks, respectively. ChIP-seq is an effective tool to study global protein-DNA interactions. To study global epigenetic differences, we used H3K4Me3 antibody to evaluate its enrichment in pancreatic acinar cells of WT and Mist1-/- mice followed by next generation sequencing. We found specific hotspots that showed differential enrichment for H3K4Me3 both in WT and Mist1-/- mice. The data show that pancreatic acinar cells are epigenetically reprogrammed under stressed cellular conditions. Global H3K4Me3 profiling of WT and Mist1-/- pancreatic acinar cells using ChIP-seq.
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