Utility of CT Radiomics Features in Differentiation of Pancreatic Ductal Adenocarcinoma From Normal Pancreatic Tissue

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide therapy. The aim of this study was to determine the feasibility of MUC1-based targeted radionuclide therapy for PDAC, by evaluating the expression profile of MUC1 in different pancreatic cells and tissues using the C595 antibody. MUC1 expression was evaluated in four PDAC cell lines (PANC-1, BxPC-3, CAPAN-1 and AsPC-1) using flow cytometry and immunocytochemistry. Immunohistochemistry was performed on primary and metastatic PDAC, pancreatitis, pancreatic intra-epithelial neoplasia and normal pancreatic tissue samples to identify potential changes in C595-reactive MUC1 expression across different disease groups. C595-reactive MUC1 expression was found to varying degrees in the cell lines (11.5–93.1%). A pixel analysis of the immunohistochemical staining demonstrated highest MUC1 expression in primary PDAC tissue (mean pixel value of 205.4), followed by other pancreatic cancer types (204.9), pancreatic intra-epithelial neoplasia (203.8), metastatic PDAC (201.5), chronic pancreatitis (198.1) and normal pancreatic tissue (191.4). The increased expression in malignant tissues and reduced expression in benign tissues indicate that C595-reactive MUC1 is a potential target for targeted radionuclide therapy of PDAC.

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Immunohistochemical expression of NEDD9, E-cadherin and γ-catenin and their prognostic significance in pancreatic ductal adenocarcinoma (PDAC)

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2018.2378 ◽

2018 ◽

Vol 18 (3) ◽

pp. 246-251 ◽

Cited By ~ 2

Author(s):

Petra Radulović ◽

Božo Krušlin

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Patient Survival ◽

Negative Impact ◽

Prognostic Significance ◽

Pancreatic Tissue ◽

Ductal Adenocarcinoma ◽

Clinicopathological Parameters ◽

Rank Test ◽

Normal Pancreatic Tissue ◽

E Cadherin

Extensive research is being conducted to identify novel diagnostic, predictive and prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC), as only a few markers have been routinely used so far with limited success. Our aim was to assess the expression of neural precursor cell expressed developmentally down-regulated protein 9 (NEDD9), E-cadherin, and γ-catenin in PDAC in relation to clinicopathological parameters and patient survival. We also investigated if there is a correlation of NEDD9 expression with E-cadherin or γ-catenin. The protein expression was determined by immunohistochemistry in 61 PDAC and 61 samples of normal pancreatic tissue. The log rank test and Kaplan-Meier survival curve were used for survival analysis. E-cadherin and γ-catenin expressions were reduced in PDAC, and completely retained in normal pancreatic tissue. Expression of NEDD9 was significantly increased in PDAC (strong expression in 78.7% of cases and moderate in 21.3%) and reduced in normal pancreatic tissue (strong positivity in 45.9% of cases, moderate in 31.1%, and weak in 23%). There was a positive correlation between reduced E-cadherin and γ-catenin expression in PDAC (p = 0.015). The loss or reduced expression of E-cadherin had a negative impact on patient survival (p = 0.020). A negative correlation between E-cadherin expression and tumor grade was also observed (p = 0.011). Decreased E-cadherin expression was more common in male patients with PDAC (81.3% vs. 60% for females, p = 0.005). γ-catenin and NEDD9 expressions were not statistically correlated with tumor stage and grade, gender, nor with patient survival. Our results support the role of NEDD9, E-cadherin and γ-catenin proteins in PDAC, but further research should clarify in detail their mechanism of action in pancreatic cancer.

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The WNT5A/ROR2 signaling pathway in pancreatic ductal adenocarcinoma (PDAC)

10.21203/rs.3.rs-34447/v1 ◽

2020 ◽

Author(s):

Lydia Remtisch ◽

Georg Wiltberger ◽

Katrin Schierle ◽

Moulla Yousef ◽

René Thieme ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Prognostic Value ◽

Expression Patterns ◽

Tumor Stroma ◽

Pancreatic Tissue ◽

Ductal Adenocarcinoma ◽

Normal Pancreatic Tissue ◽

Variable Expression ◽

Wnt5a Expression

Abstract Background WNT5A/ROR2 signaling pathway has been shown to be involved in many human cancers. Its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified yet. The aim of this study was to determine the prognostic value of WNT5A-expression in conjunction with the ROR2-expression in the same tumor tissues of PDAC patients. Methods We retrospectively analyzed the expression of WNT5A and ROR2 in 117 paraffin-embedded PDAC specimens following surgical pancreatic resection by immunohistochemistry. The prognostic value of WNT5A and ROR2 was assessed using Kaplan-Meier survival curves and multivariate COX regression-models. Results High ROR2-expression was detected in 65.8% (77/117) of PDAC-tumors, in 28.2% (33/117) in tumor-stroma, and in 71.1% (65/90) of normal pancreatic tissue. High WNT5A-expression was found in 76.9% (90/117) of tumors, in 59.0% (69/117) of tumor-stroma, and in 83.0% (73/88) of normal pancreatic tissue. Spearman's correlation co-efficiency demonstrated weak association between ROR2- and WNT5A-expression in tumor (r = 0.184; p = 0.047), and no association in stroma (r = 0.036; p = 0.699). Multivariate analysis showed that regional lymph node invasion and differentiation were independent prognostic factors of survival, while ROR2- and WNT5A-expression not. Conclusions Variable expression patterns for ROR2 and WNT5A were demonstrated in PDAC and normal pancreatic tissues suggesting a role for WNT5A/ROR2 signalling pathway, not only in PDAC but also in the normal pancreatic tissue during inflammation. The lack of prognostic significance for ROR2- and WNT5A-expression in our cohort, either alone or in subgroup analysis, signifies the complexity of their role in PDAC, which is highly dependent on the different molecular receptor-ligand tissue contexts.

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Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

Biological Chemistry ◽

10.1515/hsz-2016-0138 ◽

2016 ◽

Vol 397 (9) ◽

pp. 871-881 ◽

Cited By ~ 6

Author(s):

Anthony J. O’Donoghue ◽

Sam L. Ivry ◽

Chaity Chaudhury ◽

Daniel R. Hostetter ◽

Douglas Hanahan ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Immunoblot Analysis ◽

Pancreatic Tissue ◽

Tumor Burden ◽

Ductal Adenocarcinoma ◽

Aspartyl Protease ◽

Altered Expression ◽

Cathepsin E ◽

Stage Disease ◽

End Stage

Abstract The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection.

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Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma

Cells ◽

10.3390/cells10081856 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1856

Author(s):

Maria Dobre ◽

Vlad Herlea ◽

Cătălina Vlăduţ ◽

Mihai Ciocîrlan ◽

Vasile Daniel Balaban ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Treatment Options ◽

Therapy Resistance ◽

Pancreatic Disease ◽

Pancreatic Tissue ◽

Ductal Adenocarcinoma ◽

Normal Tissues ◽

Pdac Tissue

Background: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway. Method: We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue). Results: We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues. Conclusions: We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.

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Differential Diagnosis of pancreatic ductal adenocarcinoma based on differential expression of select miRNA in pancreatic tissue and plasma

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.lb526 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Rafael Zimak Figueiredo ◽

Nivaldo Farias Vieira ◽

Mucio Luiz Assis Cirino ◽

Fermino Sanches Lizarte Neto ◽

Alberto Facury Gaspar ◽

...

Keyword(s):

Differential Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Differential Expression ◽

Pancreatic Tissue ◽

Ductal Adenocarcinoma

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MicroRNAs Deregulated in Intraductal Papillary Mucinous Neoplasm Converge on Actin Cytoskeleton-Related Pathways That Are Maintained in Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers13102369 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2369

Author(s):

Elena Fernandez-Castañer ◽

Maria Vila-Casadesus ◽

Elena Vila-Navarro ◽

Carolina Parra ◽

Juan Jose Lozano ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Pancreatic Ductal Adenocarcinoma ◽

Cell Structure ◽

Mrna Translation ◽

Pancreatic Tissue ◽

Functional Enrichment ◽

Ductal Adenocarcinoma ◽

Mirna Regulation ◽

Pancreatic Cell ◽

Potential Implication

Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can develop into pancreatic ductal adenocarcinoma (PDAC). Although there is an increasing incidence of IPMN diagnosis, the mechanisms of formation and progression into invasive cancer remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs, repressors of mRNA translation, and promising diagnostic biomarkers for IPMN and PDAC. Functional information on the role of early-altered miRNAs in this setting would offer novel strategies for tracking the IPMN-to-PDAC progression. In order to detect mRNAs that are likely to be under miRNA regulation in IPMNs, whole transcriptome and miRNome data from normal pancreatic tissue (n = 3) and IPMN lesions (n = 4) were combined and filtered according to negative correlation and miRNA-target prediction databases by using miRComb R package. Further comparison analysis with PDAC data allowed us to obtain a subset of miRNA-mRNA pairs shared in IPMN and PDAC. Functional enrichment analysis unravelled processes that are mainly related with cell structure, actin cytoskeleton, and metabolism. MiR-181a appeared as a master regulator of these processes. The expression of selected miRNA-mRNA pairs was validated by qRT-PCR in an independent cohort of patients (n = 40), and then analysed in different pancreatic cell lines. Finally, we generated a cellular model of HPDE cells stably overexpressing miR-181a, which showed a significant alteration of actin cytoskeleton structures accompanied by a significant downregulation of EPB41L4B and SEL1L expression. In situ hybridization of miR-181a and immunohistochemistry of EPB41L4B and SEL1L in pancreatic tissues (n = 4 Healthy; n = 3 IPMN; n = 4 PDAC) were also carried out. In this study, we offer insights on the potential implication of miRNA alteration in the regulation of structural and metabolic changes that pancreatic cells experience during IPMN establishment and that are maintained in PDAC.

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Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

Cancers ◽

10.3390/cancers13143431 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3431

Author(s):

Ruben Bellotti ◽

Cornelia Speth ◽

Timon E. Adolph ◽

Cornelia Lass-Flörl ◽

Maria Effenberger ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Intestinal Flora ◽

Treatment Strategies ◽

Fusobacterium Nucleatum ◽

Pancreatic Tissue ◽

Individual Variability ◽

Ductal Adenocarcinoma

Background: Dysbiosis of the intestinal flora has emerged as an oncogenic contributor in different malignancies. Recent findings suggest a crucial tumor-promoting role of micro- and mycobiome alterations also in the development of pancreatic ductal adenocarcinoma (PDAC). Methods: To summarize the current knowledge about this topic, a systematic literature search of articles published until October 2020 was performed in MEDLINE (PubMed). Results: An increasing number of publications describe associations between bacterial and fungal species and PDAC development. Despite the high inter-individual variability of the commensal flora, some studies identify specific microbial signatures in PDAC patients, including oral commensals like Porphyromonas gingivalis and Fusobacterium nucleatum or Gram-negative bacteria like Proteobacteria. The role of Helicobacter spp. remains unclear. Recent isolation of Malassezia globosa from PDAC tissue suggest also the mycobiota as a crucial player of tumorigenesis. Based on described molecular mechanisms and interactions between the pancreatic tissue and the immune system this review proposes a model of how the micro- and the mycobial dysbiosis could contribute to tumorigenesis in PDAC. Conclusions: The presence of micro- and mycobial dysbiosis in pancreatic tumor tissue opens a fascinating perspective on PDAC oncogenesis. Further studies will pave the way for novel tumor markers and treatment strategies.

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Altered DNA methylation in ion transport and immune signalling genes is associated with severity in Pancreatic Ductal Adenocarcinoma

10.1101/2021.06.14.448193 ◽

2021 ◽

Author(s):

Ankita Chatterjee ◽

Akash Bararia ◽

Debopriyo Ganguly ◽

Paromita Roy ◽

Sudeep Banerjee ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Pancreatic Ductal Adenocarcinoma ◽

Pancreatic Tissue ◽

Differential Methylation ◽

Ductal Adenocarcinoma ◽

P Value ◽

Tissue Samples ◽

Normal Tissues ◽

Transcription Regulators

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cancers worldwide and has a poor survival, with a relative five-year survival rate of only 8.5%. In this study we investigated epigenetic marks associated with PDAC severity and prognosis, through studying alterations in DNA methylation patterns. Methods: DNA methylome for tumor and adjacent normal tissue samples from PDAC patients (n=7) were generated using Illumina 450K bead chips. Differentially methylated positions (DMPs) were identified with |delta beta| > 0.2 and p-value<0.01 by comparing tumors with the adjacent normal tissues. Validation of differential methylation and associated gene expression at selected genes was carried out in an independent cohort PDAC patient. Results: We identified 76 DMPs in PDAC patients that mapped to 43 genes. Among them, 44.7% (n=34) were hypo-methylated and 55.3% (n=42) were hyper-methylated DMPs in cancer samples. The trends of change in methylation at these 76 DMPs from well to moderate were like that from moderate to poorly differentiated cancer samples. The gradual trend in differential methylation was observed both in our cohort and the TCGA-PAAD cohort, suggesting methylation marks can serve as early indicators of disease pathology. Altered promoter methylation, which may affect gene expression, was observed for transcription regulators (BHLHE23, GSC2, FOXE1 and TWIST1), gated ion channels (KCNA6, and CACNB2), tumor suppressors (RASSF1, SPRED2, and NPY) and genes functioning in interferon signalling (SIGIRR, MX2, and OAS2). We also have compared the TCGA-PAAD dataset with normal pancreatic tissue data from GTEx V8 dataset leading to a confluent observation. Conclusions: We reported the first study on methylome in PDAC tumors from patients in India. We identified altered DNA methylation associated with increasing severity in PDAC among some genes like SIGIRR, MX2 along with other previously reported loci. We also concluded a confluence in our observation when comparing the TCGA-PAAD dataset with GTEx V8 dataset.

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Integrin alpha 2 (Itga2), CD49b, is differentially expressed in pancreatic ductal adenocarcinoma.

10.31219/osf.io/4jwq8 ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

United States ◽

Pancreatic Ductal Adenocarcinoma ◽

Cell Adhesion Molecule ◽

Pancreatic Tumor ◽

The United States ◽

Pancreatic Tissue ◽

Ductal Adenocarcinoma ◽

Novel Therapies ◽

Tissue Of Origin ◽

Level Analysis

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death from cancer in the United States (1, 2). Novel therapies are required to extend survival in PDAC and systems-level analysis of the tumors transcriptome as compared to the tissue of origin can reveal the basic transcriptional nature of tumors and how they differ from the tissue in which they reside and from which they originate (3). In this study, we compared the transcriptome of PDAC tumors isolated from patients with PDAC as compared to healthy, non-affected pancreatic tissue using two separate datasets (4, 5). We found that the cell adhesion molecule integrin alpha 2 (Itga2), also known as CD49b, was among the genes whose expression was most significantly different between PDAC and the benign pancreas. Itga2 expression was significantly higher in PDAC tumors compared to non-affected pancreatic tissue. Pancreatic ductal adenocarcinomas increase the expression of Itga2 during the transition from benign pancreatic tissue to transformed pancreatic tumor.

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