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Quantitative structural analysis of glycans expressed within tumors derived from pancreatic cancer patient-derived
Kayo Hasehira1, Tomoaki Furuta2, Osamu Shimomura2
1Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is an intractable malignancy for which novel therapeutic targets are in high demand. To uncover glycans expressed within PDAC, we previously performed glycome profiling of PDAC cell lines using lectin microarray and found that the lectin rBC2LCN with specificity to a Fucα1-2Galβ1-3 motif exhibited strong binding to a PDAC cell line (Capan-1) and to all tumor tissues derived from 69 pancreatic cancer patients. Nevertheless, no information was available as to whether glycans containing the Fucα1-2Galβ1-3 motif are expressed within PDAC. Here we used HPLC combined with MALDI-TOFMS to perform a structural and quantitative glycome analysis targeting both N- and O-glycans derived from two types of patient-derived PDAC xenograft mouse models, PC3 (well-differentiated) and PC42 (poorly-differentiated). A higher percentage of highly branched and sialylated complex-type N-glycans was detected in PC42 relative to PC3. The percentage of core 1 O-glycans was higher in PC42 relative to PC3, whereas that of core 3 O-glycans was higher in PC3. Cancer-related glycan epitopes such as Lewis A and Lewis Y were detected in core 3 O-glycans of both PC3 and PC42. H-type3 containing the Fucα1-2Galβ1-3 motif was detected in Core 2 O-glycans in both models, explaining the molecular mechanism of the binding of rBC2LCN to PDAC.
Insights
Researchers identified specific glycans in pancreatic cancer, explaining how a lectin binds to tumors. This finding advances understanding of pancreatic ductal adenocarcinoma (PDAC) and potential therapeutic targets.
Area of Science:
- Biochemistry
- Glycomics
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) requires new therapeutic targets.
- Previous lectin microarray identified a binding motif (Fucα1-2Galβ1-3) in PDAC cells and patient tumors.
- The presence of this specific glycan motif in PDAC was previously unconfirmed.
Purpose of the Study:
- To structurally and quantitatively analyze N- and O-glycans in PDAC.
- To identify the presence and location of the Fucα1-2Galβ1-3 glycan motif in PDAC.
- To elucidate the molecular mechanism behind lectin rBC2LCN binding to PDAC.
Main Methods:
- Utilized High-Performance Liquid Chromatography (HPLC) combined with Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOFMS).
- Analyzed both N-glycans and O-glycans.
- Employed two patient-derived PDAC xenograft mouse models: PC3 (well-differentiated) and PC42 (poorly-differentiated).
Main Results:
- PC42 models showed higher percentages of branched, sialylated N-glycans and core 1 O-glycans compared to PC3.
- PC3 models exhibited higher percentages of core 3 O-glycans.
- Cancer-related epitopes Lewis A and Lewis Y were found in core 3 O-glycans.
- H-type3, containing the Fucα1-2Galβ1-3 motif, was detected in core 2 O-glycans in both models.
Conclusions:
- The study confirms the expression of the Fucα1-2Galβ1-3 glycan motif in PDAC.
- This glycan motif, specifically H-type3 in core 2 O-glycans, explains the binding of lectin rBC2LCN to PDAC.
- These findings provide insights into PDAC glycan expression and potential therapeutic strategies.
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