Inhibition of sialyltransferases in pancreatic cancer: effects on the EGFR pathway and on the tumour phenotype

Pancreatic ductal adenocarcinoma (PDA) presents a dismal prognosis mainly due to its delayed diagnosis, its aggressiveness, and resistance to existing therapies. Aberrant glycosylation and, in particular, the overexpression of several sialylated determinants such as sialyl-Lewisx/a (sLex/a), have been associated to cancer progression and metastatic spread, in addition to the modulation of the immune cell component of the tumour microenvironment. Previous studies from our group demonstrated that the α2,3-sialyltransferases (ST) ST3GAL3 and ST3GAL4, two enzymes that transfer sialic acid (SA) to generate α2,3-sialylated determinants, promote the invasive and metastatic phenotype of PDA cell lines. In addition, these enzymes were shown to sialylate cell adhesion molecules involved in tumour progression, such as α2β1 integrin and E-cadherin, regulating their function and signalling pathways. These findings, together with the fact that expression levels of STs and SA levels are generally increased in the serum of cancer patients, being indicative of poor prognosis, highlight the importance of reducing hypersialylation in PDA. Blocking sialylation by modifying ST mRNA expression or by sialidase treatment has been used to study the role of tumour SA, but the application of these approaches to the clinical setting is complex. Nonetheless, the recent discovery and development of ST inhibitors have represented a new strategy to pharmacologically inhibit SA expression in tumours and have opened a path to therapeutically target STs. The Epidermal Growth Factor Receptor (EGFR), an important membrane receptor involved in cell proliferation, contributes to several processes favouring cancer onset, progression, and metastatic spread in nearly all neoplasms, including PDA. EGFR is a glycoprotein membrane receptor that can be sialylated by STs that, in turn, can modulate its function. In this regard, the study of EGFR glycosylation in different cancer types has recently increased, although the role of EGFR sialylation in PDA progression is still unclear, and would be of high interest for scientists developing EGFR-targeted therapies. Under these premises, in this study we principally aimed to gain insight into the role of the STs and their generated tumour sialoglycans on the phenotype of PDA cells; as well as to study their effect on the function and signalling of EGFR ​
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