Discovery of Pancreatic Ductal Adenocarcinoma-Related Aberrant Glycosylations: A Multilateral Approach of Lectin Microarray-Based Tissue Glycomic Profiling With Public Transcriptomic Datasets

Wagatsuma, Takanori; Nagai‐Okatani, Chiaki; Matsuda, Atsushi; Masugi, Yohei; Imaoka, Masako; Yamazaki, Ken; Sakamoto, Michiie; Kuno, Atsushi

doi:10.3389/fonc.2020.00338

Cited by 20 publications

(24 citation statements)

References 56 publications

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“…Looking at the average relative abundance in PXO models, we find that the top 10 N-glycans (Figure 6E) collectively contributed to approximately 60% of total abundance. Among these, there were 5 high-mannose glycans (H8N2, H5N2, H6N2, H7N2, H9N2), consistent with previous studies reporting increased levels of high-mannose glycans in pancreatic tumor regions, compared with normal tissues, detected by MALDI imaging mass spectrometry (23,24) or by lectin probing (25). Four other In vivo tumor responses were reassessed using modified RESIST criteria and categorized as complete response (CR), partial response (PR), and progressive disease (PD).…”

Section: Resultssupporting

confidence: 91%

PDX-derived organoids model in vivo drug response and secrete biomarkers

et al. 2020

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Section: Resultssupporting

confidence: 91%

PDX-derived organoids model in vivo drug response and secrete biomarkers

et al. 2020

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“…These include prominent increases in a-2,3and a-2,6-sialosides, bisecting GlcNAc, and poly-LacNAc epitopes. Similar shifts in sialylation and bisecting GlcNAc levels were observed in work comparing the glycome of pancreatic cancer to patient-matched adjacent-tissue (19). However, changes in core fucosylation, which emerged in both our glycomic analysis and transcriptomic analysis, was not replicated in the KC mouse model.…”

Section: Discussionsupporting

confidence: 70%

“…For our analysis, we obtained 12 biopsy samples from non-cancerous pancreata and 12 from pancreatic adenocarcinoma (PDA) of patients (SI Appendix, Table S1). Previous glycomic analysis on pancreatic cancer used "normal adjacent" tissue, but this is not considered representative of the non-transformed pancreas (19,20). In brief, formalin-fixed paraffin embedded (FFPE) pancreatic tissue samples were solubilized and labeled with Alexa Fluor 555-NHS as previously described (SI Appendix, Table S2) (15).…”

Section: Human Pancreatic Cancer Displays Strong Shifts In the Glycomementioning

confidence: 99%

Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1

Kurz

Chen

Vucic

et al. 2021

Preprint

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Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-death in the U.S.. Glycans, such as CA-19-9, are biomarkers of PDA and are emerging as important modulators of cancer phenotypes. Herein, we utilized a systems-based approach integrating glycomic analysis of human PDA and the well-established KC mouse model, with transcriptomic data to identify and probe the functional significance of aberrant glycosylation in pancreatic cancer. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of α-2,3- and α-2,6-sialic acids, bisecting GlcNAc and poly-LacNAc. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes can be modeled in the KC mouse. In silico analysis of bulk and single cell sequencing data identified ST6GAL1, which underlies α-2,6-sialic acid, as overexpressed in human PDA, concordant with histological data. Enzymes levels correlated with the stage of clinical disease. To test whether ST6GAL1 promotes pancreatic cancer we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. Analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems-approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.

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“…Immunoprecipitation was performed as described previously ( 21 ). Briefly, 200 µg of prepared cell lysates and 50 µl of tissue lysates (corresponding to about 8 mm 2 ) were subjected to immunoprecipitation using biotinylated-mouse-anti-ERC/MSLN antibody (IBL, clone 22A31, #10357).…”

Section: Methodsmentioning

confidence: 99%

Bisecting-GlcNAc on Asn388 is characteristic to ERC/mesothelin expressed on epithelioid mesothelioma cells

Fujihira

Takakura

Matsuda

et al. 2021

The Journal of Biochemistry

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Mesothelioma is a highly aggressive tumor associated with asbestos exposure and is histologically classified into three types: epithelioid-type, sarcomatoid-type, and biphasic-type. The prognosis of mesothelioma patients is poor and there is no effective molecular-targeting therapy as yet. ERC/mesothelin is a glycoprotein that is highly expressed on several types of cancers including epithelioid mesothelioma, but also expressed on normal mesothelial cells. This is a predicted reason why there is no clinically approved therapeutic antibody targeting ERC/mesothelin. In the present study, we focused on the differential glycosylation between ERC/mesothelin present on epithelioid mesothelioma and that on normal mesothelial cells and aimed to reveal a distinct feature of epithelioid mesothelioma cells. Lectin microarray analysis of ERC/mesothelin using cells and patient specimens showed significantly stronger binding of PHA-E4 lectin, which recognizes complex-type N-glycans having a so-called bisecting-GlcNAc structure, to ERC/mesothelin from epithelioid mesothelioma cells than that from normal mesothelial cells. Further, LC/MS analysis on ERC/mesothelin from epithelioid mesothelioma cells confirmed the presence of a bisecting-GlcNAc attached to Asn388 of ERC/mesothelin. These results suggest that this glycoproteome could serve as a potential target for the generation of a highly selective and safe therapeutic antibody for epithelioid mesothelioma.

show abstract

Discovery of Pancreatic Ductal Adenocarcinoma-Related Aberrant Glycosylations: A Multilateral Approach of Lectin Microarray-Based Tissue Glycomic Profiling With Public Transcriptomic Datasets

Cited by 20 publications

References 56 publications

PDX-derived organoids model in vivo drug response and secrete biomarkers

PDX-derived organoids model in vivo drug response and secrete biomarkers

Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1

Bisecting-GlcNAc on Asn388 is characteristic to ERC/mesothelin expressed on epithelioid mesothelioma cells

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