Analysis of Single Nuclear Chromatin Accessibility Demonstrates Unique Myeloid Populations Differentially Influence Prognosis in Human Pancreatic Ductal Adenocarcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241896 | GEO | 2024/02/15
REPOSITORIES: GEO
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Project description:Background: A better understanding of the pancreatic adenocarcinoma (PDAC) immune microenvironment is critical to improving outcomes. Myeloid cells are of particular importance for PDAC progression. Circulating monocytes are recruited and hijacked by the tumor to become immune suppressive tumor-associated macrophages. Meanwhile, tissue resident macrophages are innately anti-inflammatory and pro-fibrotic. Open chromatin and transcription factor activity provide source and function data for myeloid cells. Thus, we explore single nuclear assay for transposase accessible chromatin (ATAC) sequencing (snATAC-Seq), a method to analyze open gene promoters and transcription factor binding, as an important means for discerning the myeloid composition in human PDAC tumors. Methods: Frozen pancreatic tissues (benign or PDAC) were digested into single nuclei suspensions. snATAC-Seq and sn-Multiome (ATAC + RNA) libraries were prepared using 10X Chromium technology and sequenced by an Illumina sequencer. Signac was used for preliminary analysis, clustering, and differentially accessible chromatin region identification. snMultiome data was used to validate cell annotations for the snATAC-Seq data. Results: Unique populations comprised the benign and tumor samples. Myeloid cell transcription factor activities were higher in tumor samples than benign pancreatic samples, enabling us to further stratify myeloid populations in PDAC tumors. GO enrichment analysis showed myeloid cells can activate immune response in tumors. Subcluster analysis revealed eight distinct myeloid populations. GO enrichment demonstrated unique functions of different myeloid populations, including IL-1b signaling (recruited monocytes) and intracellular protein transport (dendritic cells). Conclusions: These data suggest snATAC-Seq as a method for retrospective analysis of frozen human pancreatic tissues to identify myeloid populations. Understanding the source specific potential function of myeloid cells is important for patient prognosis in PDAC.
2024-02-15 | GSE241895 | GEO
Project description:Background: A better understanding of the pancreatic adenocarcinoma (PDAC) immune microenvironment is critical to improving outcomes. Myeloid cells are of particular importance for PDAC progression. Circulating monocytes are recruited and hijacked by the tumor to become immune suppressive tumor-associated macrophages. Meanwhile, tissue resident macrophages are innately anti-inflammatory and pro-fibrotic. Open chromatin and transcription factor activity provide source and function data for myeloid cells. Thus, we explore single nuclear assay for transposase accessible chromatin (ATAC) sequencing (snATAC-Seq), a method to analyze open gene promoters and transcription factor binding, as an important means for discerning the myeloid composition in human PDAC tumors. Methods: Frozen pancreatic tissues (benign or PDAC) were digested into single nuclei suspensions. snATAC-Seq and sn-Multiome (ATAC + RNA) libraries were prepared using 10X Chromium technology and sequenced by an Illumina sequencer. Signac was used for preliminary analysis, clustering, and differentially accessible chromatin region identification. snMultiome data was used to validate cell annotations for the snATAC-Seq data. Results: Unique populations comprised the benign and tumor samples. Myeloid cell transcription factor activities were higher in tumor samples than benign pancreatic samples, enabling us to further stratify myeloid populations in PDAC tumors. GO enrichment analysis showed myeloid cells can activate immune response in tumors. Subcluster analysis revealed eight distinct myeloid populations. GO enrichment demonstrated unique functions of different myeloid populations, including IL-1b signaling (recruited monocytes) and intracellular protein transport (dendritic cells). Conclusions: These data suggest snATAC-Seq as a method for retrospective analysis of frozen human pancreatic tissues to identify myeloid populations. Understanding the source specific potential function of myeloid cells is important for patient prognosis in PDAC.
2024-02-15 | GSE241883 | GEO
Project description:Analysis of Single Nuclear Chromatin Accessibility Demonstrates Unique Myeloid Populations Differentially Influence Prognosis in Human Pancreatic Ductal Adenocarcinoma
| PRJNA1010705 | ENA
Project description:BackgroundA better understanding of the pancreatic ductal adenocarcinoma (PDAC) immune microenvironment is critical to developing new treatments and improving outcomes. Myeloid cells are of particular importance for PDAC progression; however, the presence of heterogenous subsets with different ontogeny and impact, along with some fluidity between them, (infiltrating monocytes vs. tissue-resident macrophages; M1 vs. M2) makes characterisation of myeloid populations challenging. Recent advances in single cell sequencing technology provide tools for characterisation of immune cell infiltrates, and open chromatin provides source and function data for myeloid cells to assist in more comprehensive characterisation. Thus, we explore single nuclear assay for transposase accessible chromatin (ATAC) sequencing (snATAC-Seq), a method to analyse open gene promoters and transcription factor binding, as an important means for discerning the myeloid composition in human PDAC tumours.MethodsFrozen pancreatic tissues (benign or PDAC) were prepared for snATAC-Seq using 10× Chromium technology. Signac was used for preliminary analysis, clustering and differentially accessible chromatin region identification. The genes annotated in promoter regions were used for Gene Ontology (GO) enrichment and cell type annotation. Gene signatures were used for survival analysis with The Cancer Genome Atlas (TCGA)-pancreatic adenocarcinoma (PAAD) dataset.ResultsMyeloid cell transcription factor activities were higher in tumour than benign pancreatic samples, enabling us to further stratify tumour myeloid populations. Subcluster analysis revealed eight distinct myeloid populations. GO enrichment demonstrated unique functions for myeloid populations, including interleukin-1b signalling (recruited monocytes) and intracellular protein transport (dendritic cells). The identified gene signature for dendritic cells influenced survival (hazard ratio = .63, p = .03) in the TCGA-PAAD dataset, which was unique to PDAC.ConclusionsThese data suggest snATAC-Seq as a method for analysis of frozen human pancreatic tissues to distinguish myeloid populations. An improved understanding of myeloid cell heterogeneity and function is important for developing new treatment targets in PDAC.
| S-EPMC10905544 | biostudies-literature
Project description:Analysis of Single Nuclear Chromatin Accessibility Demonstrates Unique Myeloid Populations Differentially Influence Prognosis in Human Pancreatic Ductal Adenocarcinoma [snATAC]
| PRJNA1010689 | ENA
Project description:Analysis of Single Nuclear Chromatin Accessibility Demonstrates Unique Myeloid Populations Differentially Influence Prognosis in Human Pancreatic Ductal Adenocarcinoma [snMultiome]
| PRJNA1010711 | ENA
Project description:Liver kinase B1 (LKB1) has been identified as a critical modulator involved in cell proliferation and polarity. The purpose of the current study was to characterize the expression pattern of LKB1 and assess the clinical significance of LKB1 expression in pancreatic ductal adenocarcinoma (PDAC) patients. LKB1 mRNA expression which was analyzed in 32 PDAC lesions and matched non-tumor tissues, was downregulated in 50% (16/32) of PDAC lesions. Similar results were also obtained by analyzing three independent datasets from Oncomine. Protein expression of LKB1 was significantly reduced in 6 PDAC cell lines and downregulated in 31.3% (10/32) of PDAC lesions compared to matched non-tumorous tissues, as determined by Western blot analysis. Additionally, tissue microarray containing 205 PDAC specimens was evaluated for LKB1 expression by IHC and demonstrated that reduced expression of LKB1 in 17.6% (36/205) of PDAC tissues was significantly correlated with clinical stage, T classification, N classification, liver metastasis and vascular invasion. Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of PDAC and found that LKB1 protein expression was one of the independent prognostic factors for overall survival of PDAC patients.
| S-EPMC4650682 | biostudies-other
Project description:BackgroundThe prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial.MethodsHaematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm2 field of view and additionally in 10 high-power fields (HPF) (HPF = 0.238 mm2).ResultsTumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018-1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut-offs for tumour budding in colorectal cancer were prognostic in PDAC as well.ConclusionsTumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary.
| S-EPMC5988658 | biostudies-literature
Project description:Using integrative genomics and functional screening, we identified coiled-coil domain containing 68 (CCDC68) as a novel putative tumor suppressor gene (TSG) in pancreatic ductal adenocarcinoma (PDAC). CCDC68 allelic losses were documented in 48% of primary PDAC patient tumors, 50% of PDAC cell lines and 30% of primary patient derived xenografts. We also discovered a single nucleotide polymorphism (SNP) variant (SNP rs1344011) that leads to exon skipping and generation of an unstable protein isoform CCDC68Δ(69-114) in 31% of PDAC patients. Overexpression of full length CCDC68 (CCDC68(wt)) in PANC-1 and Hs.766T PDAC cell lines lacking CDCC68 expression decreased proliferation and tumorigenicity in scid mice. In contrast, the downregulation of endogenous CCDC68 in MIAPaca-2 cells increased tumor growth rate. These effects were not observed with the deletion-containing isoform, CCDC68Δ(69-114).
| S-EPMC5153324 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC), accounting for 90-95% of all pancreatic tumors, is a highly devastating disease associated with poor prognosis. The lack of accurate diagnostic tests and failure of conventional therapies contribute to this pejorative issue. Over the last decade, the advent of theranostics in nuclear medicine has opened great opportunities for the diagnosis and treatment of several solid tumors. Several radiotracers dedicated to PDAC imaging or internal vectorized radiotherapy have been developed and some of them are currently under clinical consideration. The functional information provided by Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) could indeed provide an additive diagnostic value and thus help in the selection of patients for targeted therapies. Moreover, the therapeutic potential of β-- and α-emitter-radiolabeled agents could also overcome the resistance to conventional therapies. This review summarizes the current knowledge concerning the recent developments in the nuclear medicine field for the management of PDAC patients.
| S-EPMC8232627 | biostudies-literature