Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer

Bauer, Andrea S.; Nazarov, Petr V.; Giese, Nathalia A.; Beghelli, Stefania; Heller, Anette; Greenhalf, William; Costello, Eithne; Muller, Arnaud; Bier, Melanie; Strobel, Oliver; Hackert, Thilo; Vallar, Laurent; Scarpa, Aldo; Büchler, Markus W.; Neoptolemos, John P.; Kreis, Stephanie; Hoheisel, Jörg D.

doi:10.1002/ijc.31087

Cited by 14 publications

(23 citation statements)

References 52 publications

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“…Consistent with recent reports (16)(17)(18), the most enriched canonical pathways associated with disease-associated fibroblasts compared to NA were phagosome maturation, autophagy and endocytosis signaling (Figure 1F). The most common biological functions differentially regulated between disease-associated fibroblasts and NA or NF corresponded to cell movement and migration with key upstream regulators such as TNF, TP53 and TGFβ1 (19-21) altered in these comparison groups (Supplementary Figure 2B, 2C).…”

Section: Disease-associated Fibroblasts From Pancreatic Pathologies Show Distinct Gene Expression Profilessupporting

confidence: 91%

Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties

et al. 2020

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Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown.Here we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors (PAT), and adjacent normal (NA) tissue (N=34) have distinct mRNA and miRNA profiles. Compared to NA-fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an anti-fibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC-and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of Tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared to CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research.

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Section: Disease-associated Fibroblasts From Pancreatic Pathologies Show Distinct Gene Expression Profilessupporting

confidence: 91%

Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties

et al. 2020

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“…In our study, pancreatic tissue samples from normal individuals were used as a control group, while other researchers used samples of paratumor tissues, which reduces the specificity of the marker, since the inflammatory process that circumscribes tumor cells can express the target in question with levels equivalent to the tumorigenic microenvironment, highlighting it in benign inflammatory conditions. Another fact that stands out in the control group, as it directly interferes with expression levels, since it is used, in many cases, as a calibrator in real-time PCR reactions (Bauer et al, 2018). miRNA-21 was analyzed in invasive pancreatic tissue and Vater papilla adenocarcinomas, comparing them to normal adjacent tissues.…”

Section: Discussionmentioning

confidence: 99%

Research Article Combination of microRNA-21 expression with the serum marker CA19-9 increases the accuracy of diagnosis of pancreatic adenocarcinoma

Filiputti¹,

Cirino²,

Neto³

et al. 2020

Genet. Mol. Res.

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Pancreatic adenocarcinoma (PA) is one of the most aggressive malignant tumors of the digestive tract, with a five-year survival rate of 5%. Early detection offers better possibilities of cure; however, in early stages it does not present symptoms, making the management of these patients difficult. The most commonly used biomarker for diagnosis of PA is serum CA19-9, which has a sensitivity between 70 and 80%, although, with less than 50% specificity, due to its expression in various other types of cancer. The reduced rate of apoptosis plays a crucial role in carcinogenesis, in which the cytotoxic attack and the effectiveness of pharmacological treatment are reduced. Therefore, it would be useful to associate the biomarker CA19-9 with other molecular tools to increase the accuracy of the diagnosis, such as microRNAs (miRNAs) that target apoptotic genes. The association between the expression profile of anti-apoptotic microRNAs (miRNA-15a and miRNA-16), proapoptotic microRNAs (miRNA-21, miRNA-221 and miRNA-222) and serum CA19-9 was evaluated for the diagnosis of pancreatic ductal adenocarcinoma. Twenty pancreatic tumor tissue samples, ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 19 (4): gmr18645 V.B. Filiputti et al. 2 after microdissection from patients diagnosed with pancreatic adenocarcinoma, were studied. As a control, seven samples of normal pancreas from cadaveric donors or patients undergoing pancreatic resection due to trauma were used. Serum CA19-9 was measured and the expression analysis of miRNA-21, miRNA-221, miRNA-222, miRNA-15a and miRNA-16 was measured using real-time quantitative PCR. The usefulness of pro-apoptotic and anti-apototic microRNAs alone or in association with CA19-9 in the diagnosis of PA was evaluated. The expression of miRNA-21 was significantly associated with PA, when compared with control samples. There was no significant difference in the expression of the other miRNAs. We conclude that association of CA19-9 and microRNA-21expression would increase sensitivity and accuracy in the diagnosis of PA.

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“…DNA methylation analysis in bulk tumor data. We used 450k DNA methylation data of cancer and normal samples from array-expression for pancreas 57 and from GEO database for lung (GSE66836) and liver (GSE54503) samples. The coordinates of 450k methylation array probes were obtained using the COHCAP library in R and were mapped to the 5kb upstream promoter region of each gene using bedtools.…”

Section: Methodsmentioning

confidence: 99%

A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and PDAC

Gopalan

Singh

Rashidi

et al. 2021

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) tumors can originate either from acinar or ductal cells in the adult pancreas. We re-analyze multiple pancreas and PDAC single-cell RNA-seq datasets and find a subset of non-malignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes up-regulated among AE cells are enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes are up-regulated in human PDAC tumors, and consistently, their promoters are hypo-methylated. High expression of these genes is associated with poor patient survival. The fraction of AE-like cells increases with age in healthy pancreatic tissue, which is not explained by clonal mutations, thus pointing to a non-genetic source of variation. We also find edge-like states in lung and liver tissues, suggesting that sub-populations of healthy cells across tissues can exist in pre-malignant states.

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Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer

Cited by 14 publications

References 52 publications

Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties

Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties

Research Article Combination of microRNA-21 expression with the serum marker CA19-9 increases the accuracy of diagnosis of pancreatic adenocarcinoma

A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and PDAC

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