Mapping the Evolution of Acinar cell derived Pancreatic Preneoplastic Lesions in a Mouse Model: A Detailed Transcriptomic and Pathological Characterization
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ABSTRACT:
PROVIDER: PRJNA1173157 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31001727.fastq.gz | Fastqsanger.gz | |||
| SRR31001728.fastq.gz | Fastqsanger.gz | |||
| SRR31001729.fastq.gz | Fastqsanger.gz | |||
| SRR31001730.fastq.gz | Fastqsanger.gz | |||
| SRR31001731.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with poor prognosis and bad therapy outcome. Therefore, mouse models are frequently used to study PDAC and pancreatic preneoplastic lesions. This study aims to evaluate a proposed progression model from acinar cells via acinar-to-ductal metaplasia (ADM) to mucinous tubular complexes (MTC) at transcriptomic level and to investigate the molecular changes behind acinar-cell derived preneoplastic lesions in a mouse model of PDAC. Methods: Spatial transcriptomics was combined with pathological characterization of preneoplastic lesions in p48Cre/+-LSL-KrasG12D/+ mice (n=5) using the 10x Visium® platform. Integration with the Mouse Cell Atlas (MCA) 2.0 single-cell dataset was performed. Bioinformatic analysis was conducted using different Python toolkits and by calculating a pseudotime along the progression axis. Findings were validated at the protein level using immunohistochemistry (IHC). Results: Transcriptional data aligned well with pathological annotations and single-cell data confirmed a decrease in acinar cells and an increase in ductal cells during ADM. Pseudotime analysis supported the progression from acinar cells via ADM to MTC, with marker gene expression patterns along this axis. Upregulation of Keratin 19 and Tetraspanin 8, and downregulation of Amylase 1 and Claudin 10, were observed. Claudin 18 was upregulated specifically in MTC, while Mesothelin and Cathepsin L peaked during ADM. Validation by IHC confirmed the expression of Keratin 19, Amylase 1, Claudin 18 and Mesothelin on protein level. Conclusions: This study confirms the development of MTC from ADM and identifies novel biomarkers along the preneoplastic progression axis in a mouse model of PDAC, advancing our understanding of early pancreatic cancer development.
2025-03-11 | GSE279507 | GEO
Project description:Basic studies on preneoplastic lesions are important to determine the molecular alterations that take place in early steps of lung carcinogenesis. Little is known about the molecular events preceding the development of lung cancer in the context of an inflammatory environment. In this study we report the generation of a chemical-induced lung carcinogenesis mouse model in the presence of silicotic chronic inflammation. Silica-induced lung inflammation, strongly promoted incidence of lung cancer in mice treated with NDMA, a carcinogen found in tobacco smoke. Histological and molecular analysis revealed that permanent inflammation contributed to lung tumorigenesis through the adquisition of preneoplastic changes in lung epithelial cells. Inflammatory milieu increased the expression of PDCD1, TGFβ-1, MCP-1, LAG3, and Foxp3 and the presence of regulatory T cells within preneoplastic lesions. In addition concomitant chronic inflammation changed the K-ras mutational profile of the generated tumors from Q61R to G12D transition. In summary, these data identify early molecular mechanisms underlying lung carcinogenesis in an inflammatory context at different steps, providing a novel approach for the identification of drivers from preneoplastic to neoplastic lesions Gene expression profile was analyzed in 11 individual lesions (8 adenomas and 3 adenocarcinomas) from the NDMA-silica treated mice and 5 lesions (2 adenomas, and 3 adenocarcinomas) from NDMA-only treated mice
2016-07-05 | E-GEOD-43453 | biostudies-arrayexpress
Project description:Microarrays were used to analyse gene expression underlying early tumourigenesis in Eker rats. Distinct classes of up- and downregulated genes were identified in different preneoplasic lesion vs. microdissected normal (healthy) renal tubules. Laser capture microdissected renal basophilic atypical tubule (bAT) and basophilic atypical hyperplasia (bAH) and healthy tissue (HT) of 6-months aristolochic acid (AA)- and ochratoxin A (OTA)-treated and control (C) male Eker rats were isolated for RNA extraction and microarray analysis in order to investigate gene expression profiles induced by AA and OTA as well as to differentiate pathways specific for the bAT to bAH progression. Keywords: gene expression study, preneoplasic lesion vs. microdissected normal renal tubules For microdissection of preneoplastic lesions from H&E stained renal cryosections, a PALM laser microdissection and pressure catapulting (LMPC) system (PALM Microlaser GmbH) was used. Atypical tubule (bAT), basophilic atypical hyperplasia (bAH) or healthy tissue (HT) were micodissected separately from each of three replicatemale Eker rats per dose group. Lesions of each type or HT from each individual animal were pooled. RNA isolation from pooled samples and subsequent Affymetrix Rat Genome RAE_230A_2.0 chip hybridization was carried out as previously described (Stemmer et al., Toxicology and Applied Pharmacology(2006) Nov 15;217(1):134-42). Time matched controls for microarrays from lesions of OTA and AA treated rats are specified as C(AA) and C(OTA).
2010-02-28 | E-GEOD-10608 | biostudies-arrayexpress
Project description:Basic studies on preneoplastic lesions are important to determine the molecular alterations that take place in early steps of lung carcinogenesis. Little is known about the molecular events preceding the development of lung cancer in the context of an inflammatory environment. In this study we report the generation of a chemical-induced lung carcinogenesis mouse model in the presence of silicotic chronic inflammation. Silica-induced lung inflammation, strongly promoted incidence of lung cancer in mice treated with NDMA, a carcinogen found in tobacco smoke. Histological and molecular analysis revealed that permanent inflammation contributed to lung tumorigenesis through the adquisition of preneoplastic changes in lung epithelial cells. Inflammatory milieu increased the expression of PDCD1, TGFβ-1, MCP-1, LAG3, and Foxp3 and the presence of regulatory T cells within preneoplastic lesions. In addition concomitant chronic inflammation changed the K-ras mutational profile of the generated tumors from Q61R to G12D transition. In summary, these data identify early molecular mechanisms underlying lung carcinogenesis in an inflammatory context at different steps, providing a novel approach for the identification of drivers from preneoplastic to neoplastic lesions
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Project description:Protein Kinase A (PKAc alpha ) regulates gastric homeostasis and preneoplastic lesions
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Project description:In this project, we utilized single-cell RNA sequencing (scRNA-seq) and MERFISH spatial transcriptomics to profile the development of pancreatic cancer in a mouse model, tracing its progression from the pre-invasive stage to full malignancy. By employing a reporter gene, we were able to dissect the heterogeneity of metaplastic acinar cells, identifying and profiling six distinct types and states of these cells. We validated their localization within pre-invasive lesions, assessed the heterogeneity across various lesions, and calculated the colocalization of different acinar metaplastic cells with stromal cells.
2026-05-01 | GSE274618 | 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:In this project, we utilized single-cell RNA sequencing (scRNA-seq) and MERFISH spatial transcriptomics to profile the development of pancreatic cancer in a mouse model, tracing its progression from the pre-invasive stage to full malignancy. By employing a reporter gene, we were able to dissect the heterogeneity of metaplastic acinar cells, identifying and profiling six distinct types and states of these cells. We validated their localization within pre-invasive lesions, assessed the heterogeneity across various lesions, and calculated the colocalization of different acinar metaplastic cells with stromal cells.
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Project description:In this project we have used single cell RNA-seq to profile pancreatic cancer development in a mouse model, from pre-invasive stage to cancer, and in human PDAC sample. Using a reporter gene, we were able to dissect metaplastic acinar cell heterogeneity, profiled six different acinar metaplastic cell types and states, validated their localization to pre-invasive lesions and correlated findings with human PDAC. In addition, we detected transcription factors, Onecut2 and Foxq1, that strictly expressed in metaplastic cells.
2020-07-31 | GSE141017 | GEO
Project description:Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies demonstrating that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole genome transcriptional profiling and compared senescent fibroblasts to their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNAi did not impact senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, demonstrating that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we demonstrate that OPN is expressed in senescent stroma within preneoplastic lesions that arise following DMBA/TPA treatment of mice, suggesting that stromal-derived OPN-mediated signaling events impact neoplastic progression.
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