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Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas

ABSTRACT: Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas

PROVIDER: PRJNA600957 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10879522_1.fastq.gz	Fastqsanger.gz
	SRR10879522_2.fastq.gz	Fastqsanger.gz
	SRR10879523_1.fastq.gz	Fastqsanger.gz
	SRR10879523_2.fastq.gz	Fastqsanger.gz
	SRR10879524_1.fastq.gz	Fastqsanger.gz

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Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

Project description:Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

| PRJNA600959 | ENA

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

Project description:Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

| PRJNA599416 | ENA

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

Project description:We applied DNA content flow cytometry to a series of adenosquamous cancer of the pancreas (ASCP) tumor samples and patient derived xenografts (PDXs). We interrogated purified sorted tumor fractions from each sample with whole genome copy number variant (CNV) and whole exome sequencing (WES) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well characterized genomic lesions including mutations in KRAS and TP53, homozygous deletion of CDKN2A, and amplification of c-MYC, that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of ASCP and pancreatic ductal adenocarcinoma (PDAC) genomes using flow sorted PDX models distinguished genes with accessible chromatin in ASCP genomes including the lysine methyltransferase SMYD2, the pancreatic cancer stem cell driver RORγ, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes. Organoids derived from these models were used to screen compounds of interest. Notably a FGFR inhibitor had significant activity against the FGFR1-ERLIN2 fusion positive PDX.

2020-01-08 | GSE143256 | GEO

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

2020-01-14 | GSE143563 | GEO

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-01-14 | GSE143565 | GEO

Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas.

Project description:Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. SIGNIFICANCE: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.

| S-EPMC7906529 | biostudies-literature

Single-cell transcriptomics of normal pancreas, intraductal papillary mucinous neoplasm, and pancreatic adenosquamous carcinoma reveals the heterogeneous progression of pancreatic ductal and stromal cells

Project description:Background: Single-cell RNA sequencing (scRNA-seq) contributes to discovering intrinsic heterogeneity of pancreatic adenosquamous carcinoma (PASC), a lethal human malignancy. However, the gene-pattern variations within ductal and stromal cells remain unclear. Methods: We fulfilled scRNA-seq profiling with one healthy donor pancreas, one intraductal papillary mucinous neoplasm (IPMN), and one PASC sample tissue. Multiple bioinformatics analyses were used to investigate the transcriptomics abnormalities from normal stage to tumor formation. Results: We identified ten subpopulations from 10,346 single cells, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and malignant cells. Within our analysis, pancreatic cancer cells were further divided into five clusters; notably, cluster 1 exhibited stem-like phenotypes, such as UBE2C, ASPM, and TOP2A. We also found that S100A2 could be a specific biomarker for tumor cells, relating to PASC progression. LGALS1, NPM1, RACK1, and PERP were upregulated gradually from ductal to malignant cells. Furthermore, the level of copy number variation in ductal and cancer cells was significantly greater than reference cells. The expression of EREG, FCGR2A, FCGR2A, and CCL4L2 increased in myeloid cells along with tumor development, while cancer-associated fibroblast could induce the immunosuppressive tumor microenvironment, promoting pancreatic cancerogenesis. Finally, we demonstrated that EGFR-associated ligand-receptor pairs were activated in stromal to malignant cell communication. Conclusion: This study revealed the variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered cellular interactions following PASC progression. Thus, we provided valuable information to further understand the crucial regulatory mechanisms that embrace the potential therapeutic targets for PASC.

2021-08-03 | GSE165399 | GEO

The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

Project description:Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a core nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein levels, or NMD efficiency. We subsequently discovered that ~40% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that UPF1 is not a common functional driver of PASC and motivate further attempts to identify unique genetic features defining these malignancies.

2020-12-19 | GSE163517 | GEO

Application of the ISM bioinformatics platform in detection of new therapeutic targets and potential therapeutic molecules

Project description:Application of EIIP / ISM bioinformatics platform in detection of new therapeutic targets and potential therapeutic molecules. Study of the molecular basis of rare human diseases

2020-12-16 | PRJEB42044 | EVA

Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer

Project description:Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer

| PRJNA594360 | ENA