Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. Here, we postulate that stromal and cancer cell compartments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates.ResultsWe analyzed native glycan fragments in 109 human FFPE PDAC samples using high mass resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI). Our method allows detection of native glycan fragments without previous digestion with PNGase or any other biochemical reaction. With this method, 8 and 18 native glycans were identified as uniquely expressed in only stromal or only cancer cell compartment, respectively. Kaplan–Meier survival model identified glycan fragments that are expressed in cancer cell or stromal compartment and significantly associated with patient outcome. Among cancer cell region-specific glycans, 10 predicted better and 6 worse patient survival. In the stroma, 1 glycan predicted good and 4 poor patient survival. Using factor analysis as a dimension reduction method, we were able to group the identified glycans in 2 factors. Multivariate analysis revealed that these factors can be used as independent survival prognostic elements with regard to the established Union for International Cancer Control (UICC) classification both in tumor and stroma regions.ConclusionOur method allows in situ detection of naturally occurring glycans in FFPE samples of human PDAC tissue and highlights the differences among glycans found in stromal and cancer cell compartment offering a basis for further exploration on the role of specific glycans in cancer–stroma communication.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date
Depending on how the sugars are attached to the protein/lipid molecule, glycoconjugates are clustered in four general groups: (i) N-linked glycoproteins where sugar motifs are attached to asparagine, (ii) O-linked glycoproteins where sugars are attached to serine/threonine, (iii) heavily glycosylated proteoglycans with one or more glycosaminoglycans (GAG) attached and (iv) glycolipids
We report on high mass resolution matrixassisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI)-based detection of prominent differences in native glycan fragments distribution among cancer and stromal compartments in human PDAC Formalin-fixed paraffin embedded (FFPE) tissue samples
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. We postulate that stromal and cancer cell com‐ partments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates. Pancreatic ductal adenocarcinoma (PDAC) remains one of the least understood malignancies to date, resulting in lack of targeted and immune-based approaches. The stroma, consisting mainly of extracellular matrix (ECM), blood vessels and ECM-producing fibroblasts, creates a setting that communicates with cancer and immune cells and modulates tumor growth, metastasis and drug resistance. Identifying molecules differentially expressed in the stroma and cancer cell compartment may allow better understanding of cancer–stroma communication and development of technologies for compartment-specific targeting and stromal modulation. Typical cancer-associated glycosylation changes include sialylation, fucosylation, O-glycan truncation and N- and
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