Altered glycosylation in pancreatic cancer and beyond

Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers and is projected to soon be the second leading cause of cancer death. Median survival of PDA patients is 6-10 mo, with the majority of diagnoses occurring at later, metastatic stages that are refractory to treatment and accompanied by worsening prognoses. Glycosylation is one of the most common types of post-translational modifications. The complex landscape of glycosylation produces an extensive repertoire of glycan moieties, glycoproteins, and glycolipids, thus adding a dynamic and tunable level of intra- and intercellular signaling regulation. Aberrant glycosylation is a feature of cancer progression and influences a broad range of signaling pathways to promote disease onset and progression. However, despite being so common, the functional consequences of altered glycosylation and their potential as therapeutic targets remain poorly understood and vastly understudied in the context of PDA. In this review, the functionality of glycans as they contribute to hallmarks of PDA are highlighted as active regulators of disease onset, tumor progression, metastatic capability, therapeutic resistance, and remodeling of the tumor immune microenvironment. A deeper understanding of the functional consequences of altered glycosylation will facilitate future hypothesis-driven studies and identify novel therapeutic strategies in PDA.

Figure 1.

The impact of aberrant glycosylation on cell signaling in PDA. O-GlcNAcylation of transcription factors catalyzed by OGT, such as Sp1, SOX2, β-catenin, YAP, and FOXO3, has been demonstrated to regulate their nuclear localization and activity. At the cell membrane, associations of mucins such as MUC16, MUC4, and MUC20 with RTKs such as EGFR, HER2, and MET have been described to modulate downstream signaling. Enzymatic activity of Neu1 on cell surface receptors has been further shown to impact receptor dimerization. Modification of receptor ligands such as Fibulin-3 (Fbln3) has also been demonstrated to increase affinity for EGFR.

Figure 2.

The impact of aberrant glycosylation alterations on cancer progression, cell adhesion, and metastasis. Disease progression in the pancreas correlates with alterations in core O- and N-glycan moieties. These include truncated O-glycans, increased sialylation, mucin deposition, Lewis blood group antigen decoration, and tumor microenvironment (TME) lectin expression. These alterations in protein and lipid glycosylation can drive changes in cell adhesion and metastasis, enabling more efficient colonization of distant organs such as the lung and liver. The secondary metastatic sites often recapitulate the altered glycosylation landscape of the primary tumor.

Figure 3.

The impact of glycosylation on the PDA immune microenvironment. The steric hindrance from aberrant glycan elongation on the cell surface of PDA cells prevents interaction with anti-tumorigenic immune cell types, providing one mechanism of tumor cell immune escape (1). Increased expression of sialyltransferases such as ST3Gal1/4 leads to increases in tumor cell surface sialic acid that act as ligands for Siglec7/9, promoting monocyte differentiation into tumor-associated macrophages (2). Expression of MUC1 has been demonstrated to promote the release of inflammatory cytokines that play roles in regulatory T cell and myeloid-derived suppressor cell chemotaxis (3). Conversely, inflammatory cytokine signals from the surrounding microenvironment influence tumor cell glycosyltransferase expression that subsequently alters glycosylation landscapes, including expression of sialylated epitopes (4).