An Immunohistochemical Evaluation of Tumor-Associated Glycans and Mucins as Targets for Molecular Imaging of Pancreatic Ductal Adenocarcinoma

Targeted molecular imaging may overcome current challenges in the preoperative and intraoperative delineation of pancreatic ductal adenocarcinoma (PDAC). Tumor-associated glycans Lea/c/x, sdi-Lea, sLea, sLex, sTn as well as mucin-1 (MUC1) and mucin-5AC (MU5AC) have gained significant interest as targets for PDAC imaging. To evaluate their PDAC molecular imaging potential, biomarker expression was determined using immunohistochemistry on PDAC, (surrounding) chronic pancreatitis (CP), healthy pancreatic, duodenum, positive (LN+) and negative lymph node (LN−) tissues, and quantified using a semi-automated digital image analysis workflow. Positive expression on PDAC tissues was found on 83% for Lea/c/x, 94% for sdi-Lea, 98% for sLea, 90% for sLex, 88% for sTn, 96% for MUC1 and 67% for MUC5AC, where all were not affected by the application of neoadjuvant therapy. Compared to PDAC, all biomarkers were significantly lower expressed on CP, healthy pancreatic and duodenal tissues, except for sTn and MUC1, which showed a strong expression on duodenum (sTn tumor:duodenum ratio: 0.6, p < 0.0001) and healthy pancreatic tissues (MUC1 tumor:pancreas ratio: 1.0, p > 0.9999), respectively. All biomarkers are suitable targets for correct identification of LN+, as well as the distinction of LN+ from LN− tissues. To conclude, this study paves the way for the development and evaluation of Lea/c/x-, sdi-Lea-, sLea-, sLex- and MUC5AC-specific tracers for molecular imaging of PDAC imaging and their subsequent introduction into the clinic.

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Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

10.1101/2020.12.07.415299 ◽

2020 ◽

Author(s):

S. Mahnaz ◽

L. Das Roy ◽

M. Bose ◽

C. De ◽

S. Nath ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathways ◽

Suppressor Cells ◽

Ductal Adenocarcinoma ◽

Myeloid Derived Suppressor Cells ◽

Mucin 1 ◽

Transmembrane Glycoprotein ◽

The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

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Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-17-2057 ◽

2018 ◽

Vol 24 (7) ◽

pp. 1574-1585 ◽

Cited By ~ 16

Author(s):

Lotfi Abou-Elkacem ◽

Huaijun Wang ◽

Sayan M. Chowdhury ◽

Richard H. Kimura ◽

Sunitha V. Bachawal ◽

...

Keyword(s):

Molecular Imaging ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Targeted Microbubbles ◽

Ultrasound Molecular Imaging

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Abstract 6194: Evaluation of the differential expression profile of CXC-receptor-2 ligands for potential biomarker candidates in pancreatic ductal adenocarcinoma

10.1158/1538-7445.am2020-6194 ◽

2020 ◽

Author(s):

Sugandha Saxena ◽

Abhilasha Purohit ◽

Evie Ehrhorn ◽

Pranita Atri ◽

Caitlin Molczyk ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Differential Expression ◽

Expression Profile ◽

Ductal Adenocarcinoma ◽

Potential Biomarker ◽

Differential Expression Profile

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Tumor-specific intraoperative detection of pancreatic ductal adenocarcinoma using multimodal molecular imaging.

HPB ◽

10.1016/j.hpb.2019.10.1487 ◽

2019 ◽

Vol 21 ◽

pp. S753

Author(s):

W. Tummers ◽

R.J. Swijnenburg ◽

S. Miller ◽

T. Teraphongphom ◽

A. Gomez ◽

...

Keyword(s):

Molecular Imaging ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Intraoperative Detection

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Integrated Bioinformatics Analysis of Gene Expression Profiles for Potential Biomarker Identification Towards Early Therapeutic Intervention in Pancreatitis and Pancreatic Ductal Adenocarcinoma

10.21203/rs.3.rs-879048/v1 ◽

2021 ◽

Author(s):

Manoj M Wagle ◽

Ananya Rao Kedige ◽

Shama P Kabekkodu ◽

Sandeep Mallya

Keyword(s):

Gene Expression ◽

Pancreatic Ductal Adenocarcinoma ◽

Bioinformatics Analysis ◽

Ductal Adenocarcinoma ◽

Rapid Progression ◽

Hub Genes ◽

Altered Expression ◽

Biochemical Pathways ◽

Potential Biomarker ◽

Key Genes

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a malignancy associated with rapid progression and an abysmal prognosis. It has been reported that chronic pancreatitis can increase the risk of developing PDAC by 16-fold. Our study aims to identify the key genes and biochemical pathways mediating pancreatitis and PDAC. The gene expression datasets were retrieved from the EMBL-EBI ArrayExpress and NCBI GEO database. A total of 172 samples of normal pancreatic tissue, 68 samples of pancreatitis, and 306 samples of PDAC were used in this study. The differentially expressed genes (DEGs) identified were used to perform downstream analysis for ontology, interaction, and associated pathways. Furthermore, hub gene expression was validated using the GEPIA2 tool and survival analysis using the Kaplan-Meier (KM) plotter. The potential druggability of the hub genes identified was determined using the Drug-Gene Interaction Database (DGIdb). Our study identified a total of 45 genes found to have altered expression levels in both PDAC and pancreatitis. Over-representation analysis revealed that protein digestion and absorption pathway, ECM-receptor interaction pathway, PI3k-Akt signaling pathway, and proteoglycans in cancer pathways as significantly enriched. Module analysis revealed 15 hub genes with 92 edges, of which 14 were found to be in the druggable genome category. Through bioinformatics analysis, we identified key genes and biochemical pathways disrupted in pancreatitis and PDAC. The results can provide new insights into targeted therapy and intervening therapeutically at an earlier stage can be used as an effective strategy to decrease the incidence and severity of PDAC.

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Identification of novel genes associated with a poor prognosis in pancreatic ductal adenocarcinoma via a bioinformatics analysis

Bioscience Reports ◽

10.1042/bsr20190625 ◽

2019 ◽

Vol 39 (8) ◽

Cited By ~ 7

Author(s):

Jun Zhou ◽

Xiaoliang Hui ◽

Ying Mao ◽

Liya Fan

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Bioinformatics Analysis ◽

Functional Enrichment ◽

Differentially Expressed ◽

Ductal Adenocarcinoma ◽

Peroxisome Proliferator ◽

Integrin Subunit ◽

Hub Genes ◽

Potential Biomarker ◽

Km Plotter

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a class of the commonest malignant carcinomas. The present study aimed to elucidate the potential biomarker and prognostic targets in PDAC. The array data of GSE41368, GSE43795, GSE55643, and GSE41369 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and differentially expressed microRNAs (DEmiRNAs) in PDAC were obtained by using GEO2R, and overlapped DEGs were acquired with Venn Diagrams. Functional enrichment analysis of overlapped DEGs and DEmiRNAs was conducted with Metascape and FunRich, respectively. The protein–protein interaction (PPI) network of overlapped DEGs was constructed by STRING and visualized with Cytoscape. Overall survival (OS) of DEmiRNAs and hub genes were investigated by Kaplan–Meier (KM) plotter (KM plotter). Transcriptional data and correlation analyses among hub genes were verified through GEPIA and Human Protein Atlas (HPA). Additionally, miRNA targets were searched using miRTarBase, then miRNA–DEG regulatory network was visualized with Cytoscape. A total of 32 DEmiRNAs and 150 overlapped DEGs were identified, and Metascape showed that DEGs were significantly enriched in cellular chemical homeostasis and pathways in cancer, while DEmiRNAs were mainly enriched in signal transduction and Glypican pathway. Moreover, seven hub genes with a high degree, namely, V-myc avian myelocytomatosis viral oncogene homolog (MYC), solute carrier family 2 member 1 (SLC2A1), PKM, plasminogen activator, urokinase (PLAU), peroxisome proliferator activated receptor γ (PPARG), MET proto-oncogene, receptor tyrosine kinase (MET), and integrin subunit α 3 (ITGA3), were identified and found to be up-regulated between PDAC and normal tissues. miR-135b, miR-221, miR-21, miR-27a, miR-199b-5p, miR-143, miR-196a, miR-655, miR-455-3p, miR-744 and hub genes predicted poor OS of PDAC. An integrative bioinformatics analysis identified several hub genes that may serve as potential biomarkers or targets for early diagnosis and precision target treatment of PDAC.

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Serum Exosomal miRNA-1226 as Potential Biomarker of Pancreatic Ductal Adenocarcinoma

OncoTargets and Therapy ◽

10.2147/ott.s296816 ◽

2021 ◽

Vol Volume 14 ◽

pp. 1441-1451

Author(s):

Cheng Wang ◽

Jianhua Wang ◽

Wenjing Cui ◽

Yongkang Liu ◽

Hao Zhou ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Potential Biomarker ◽

Exosomal Mirna

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Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma

10.1101/2020.04.29.068577 ◽

2020 ◽

Cited By ~ 1

Author(s):

Priyanka Grover ◽

Sritama Nath ◽

Mukulika Bose ◽

Alexa J. Sanders ◽

Cory Brouwer ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Mapk Pathway ◽

Tumor Promoter ◽

Ductal Adenocarcinoma ◽

Potential Biomarker ◽

Tgf Β1

AbstractPancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumor-suppressor to a tumor promoter throughout tumor development, by a yet unknown mechanism. Tumor associated MUC1 (tMUC1) is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) interacts with other oncogenic proteins promoting tumor progression and metastasis. We hypothesize that tMUC1 levels regulate TGF-β functions in PDA in vitro and in vivo. We report that high-tMUC1 expression positively correlates to TGF-βRII and negatively to TGF-βRI receptors. In response to TGF-β1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-β1 neutralizing antibody in vivo showing significantly retarded tumor growth. Analysis of clinical data from TCGA revealed significant alterations in gene-gene correlations in the TGF-β pathway in tMUC1 high versus tMUC1 low samples. This study deepens our understanding of tMUC1-regulated TGF-β’s paradoxical function in PDA and establishes tMUC1 as a potential biomarker to predict response to TGF-β-targeted therapies.

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Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

Oncology & Hematology Review (US) ◽

10.17925/ohr.2017.13.02.107 ◽

2017 ◽

Vol 13 (02) ◽

pp. 107 ◽

Cited By ~ 1

Author(s):

Andrew Hendifar ◽

Andrea Bullock ◽

◽

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Immune Cells ◽

Fluid Pressure ◽

Tumor Stroma ◽

Phase Iii ◽

Ductal Adenocarcinoma ◽

Double Blind ◽

Potential Biomarker ◽

Advanced Therapy ◽

Recombinant Human Hyaluronidase

New therapeutic approaches are urgently needed to improve survival for patients with metastatic pancreatic ductal adenocarcinoma (PDA). This carcinoma is characterized by a hyaluronan (HA)-rich desmoplastic stroma that raises tumor interstitial fluid pressure (IFP), which in turn compresses the vasculature and impedes access of anti-cancer therapies and immune cells to tumor sites. It is this biophysical barrier that is the target for PEGylated recombinant human hyaluronidase (PEGPH20; pegvorhyaluronidase alfa), which degrades HA polymers to tetra- and hexa-saccharides to remodel the tumor stroma. In preclinical models, PEGPH20 reduced IFP, and expanded tumor vasculature to improve perfusion, which increased access for innate immune cells, antibodies and therapeutic agents. The results of a phase Ib study have suggested benefits in overall survival and progression-free survival (PFS) for patients with tumors that accumulate HA (termed HA-High) treated with a combination of gemcitabine and PEGPH20. A phase II study (HALO 109-202) demonstrated that HA could be a potential biomarker for identifying patients who may be most suitable for PEGPH20 treatment. HALO 109-202 showed positive outcomes for PFS especially in HA-High patients treated with PEGPH20 plus nab-paclitaxel and gemcitabine. A randomized, double-blind, phase III study (HALO 109-301) exploring the benefits of PEGPH20 in HA-High patients with PDA is ongoing. Other PEGPH20-based combinations are being investigated in multiple stroma-rich cancers, including lung, gastric, and breast. PEGPH20 is the most advanced therapy targeting the tumor stroma and has the potential to form the therapeutic backbone for the treatment of stroma-rich tumors.

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