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Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions

ABSTRACT: The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226829 | GEO | 2023/03/08

REPOSITORIES: GEO

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Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions.

Project description:The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. We found that neoplastic lesions occur frequently in healthy organs, in donors as young as in their 3rd decade of life. Using the 10X Genomics Platform, we performed single cell RNA sequencing on 6 donor pancreata, 5 of which we separately sequenced tissue from the pancreas head and tail, for a total of 11 sequencing runs. This is a robust single-cell dataset of healthy, nonpathologic pancreas tissue and includes acinar, ductal, and non-epithelial cells (myeloid cells, fibroblasts, endothelial cells, lymphocytes). We compared this dataset of normal pancreata to single cell sequencing of tumor samples previously published in Steele, et al, Nature Cancer 2020, (raw fastq in dbGap phs002071) realigned to GRCh38 reference genome (CellRanger 6.0). This GEO series contains the raw and filtered feature matrices for the donor pancreata as well as the realigned tumor samples. Supplementary files contain the aggregate feature matrices and the metadata of the donor pancreata samples and the tumor samples.

2023-05-01 | GSE229413 | GEO

Expression Analysis of Normal and Neoplastic Mouse Pancreatic Ductal Organoids

Project description:This study used Illumina strand-specific, paired-end RNA-sequencing to examine gene expression differences between normal and neoplastic mouse pancreatic ductal cells grown as three-dimensional, organoid cultures. The study analyzed 19 independently derived organoid lines. These 19 lines included 7 biological replicate "mN," or mouse normal, organoid lines, derived from the pancreatic ductal cells of wild-type C57Bl/6J or C57Bl/6N mice. In addition, the study analyzed 6 biological replicate "mP," or mouse PanIN, organoid lines, derived from PanIN-containing mouse pancreata from the KrasLSL-G12D; Pdx1-Cre mouse model. (The presence of PanIN in the pancreata from which these organoid lines were derived was confirmed by examining histological sections from the same pancreata). The final 6 lines examined in this study were biological replicate "mT," or mouse tumor, organoid lines, derived from mouse pancreata containing pancreatic ductal adenocarcinoma (PDAC) from the KrasLSL-G12D; Trp53LSL-R162H; Pdx1-Cre mouse model. We genes differentially expressed in the PanIN- or tumor-derived mouse organoid lines, relative to the mouse normal organoids, that may reflect expression changes required for pancreatic tumorigenesis.

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A microenvironment-inspired synthetic 3D model for pancreatic ductal adenocarcinoma organoids - PDA Matrisome

Project description:LFQ analysis of matrisome fractions enriched from 12 murine PDA or PanIN samples (samples 1 - 12) and a normal pancreas pool (samples 13) pooled from 10 pancreata of C57-Bl6 animals. Three independent enrichments have been conducted for each sample with each having had four injections.

2021-11-29 | PXD022767 | Pride

Differences in gene expression in islets isolated from pancreata donated after Cardiac Death relative to Brain Death

Project description:The decreasing numbers of Donation after Brain Death (DBD) donors necessitates the comprehensive evaluation of Donation after Cardiac Death Donors (DCD) as a source of pancreata. The aim of this study was to characterize pancreata and islets from DCD and DBD donors with respect to markers of cellular stress that may indicate compromised islet quality. Immunohistochemical staining of pre-isolation pancreas biopsies found increased numbers of caspase 3 positive islets in DBD, while markers of oxidative stress (nitrotyrosine, CML, and HNE) were elevated in DCD. Assessment of islet quality by standard (yield, morphology, fluorescence microscopy, and glucose stimulated insulin secretion) and novel methods (flow cytometry, HPLC quantification of ATP) did not reveal significant differences. However, the post culture loss of DCD islets was increased compared to DBD, and DCD islets showed delayed functional potency when transplanted into diabetic NOD.scid mice. Microarray analysis of cultured islets showed increased expression of multiple stress pathway related genes in DCD compared to DBD. Together these data indicate that the current standard donor management, pancreas recovery and preservation practices are insufficient to quench the oxidative stress injury suffered by DCD islets which leads to loss in culture and may complicate their use in clinical transplant. Keywords: cell type comparison

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Secretory mucin 5AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness

Project description:Pancreatic cancer (PC) is the third deadliest malignancy with a dismal five-year survival rate. The KrasG12D initiator mutation, present in 95% of the PC patients, leads to the development of pancreatic intraepithelial neoplasia (PanIN). The PanIN lesions, the most common precursor lesion of PC, exhibit de novo expression of mucins, which significantly contributes to PC pathobiology. The poor clinical outcome of PC warrants the identification of molecular player(s) that facilitate the progression of Kras-driven precursor lesions to invasive ductal carcinoma. Gel-forming mucin 5AC (MUC5AC) is one of the top differentially expressed genes in PC as compared to the normal pancreas. The expression of MUC5AC appears de-novo at PanIN-1A stage and elevates in tumor tissues, while remaining absent in the normal pancreas. To delineate the mechanistic contribution of Muc5ac in PC pathology, we genetically depleted Muc5ac in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of PC. The onset of neoplastic growth and the progression of low-grade to high-grade PanIN lesions were significantly delayed in Muc5ac knockout (KrasG12D; Muc5ac-/-; Pdx-1cre, KCM) animals. We utilized high-throughput RNA seq. analysis to investigate the downstream molecular targets of Muc5ac-associated PC progression. Our study demonstrated that knockout of Muc5ac led to a significant decline in the genes associated with cancer stem cell (CSC) maintenance and epithelial-to-mesenchymal transition (EMT). The contribution of MUC5AC in CSC maintenance was validated via in vitro experiments, and tumor formation frequency using limiting dilution assay upon subcutaneous administration.

2020-10-25 | GSE160029 | GEO

Tissue-resident memory T cells mediate immune homeostasis in the human pancreas through the PD-1/PD-L1 pathway

Project description:We investigated the distinct state of pancreas resident memory T cells (TRM) by whole transcriptome profiling of sorted CD8+TRM cells from donor-matched pancreata, jejunum, and PLN compared to circulating blood CD8+TEM cells from living healthy donors. We identified 2029 genes differentially expressed in pancreas TRM with comparison to both PLN and jejunum TRM. Strong correlation was observed in the differentially upregulated and downregulated genes between pancreas vs. jejunum TRM and pancreas vs. PLN TRM which together define a pancreas-specific gene signature.

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Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions.

Project description:Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions.

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Project description:Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic pancreatic lesions.

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Project description:Oncogene-induced senescence in early mPanIN lesions depends on intact RelA function in vivo. We investigated the difference in gene expression between KrasG12D pancreata with and without deletion of RelA. Pancreata from 7 day old mice were prepared, RNA was isolated and Affymetrix microarray expression analysis was performed.

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