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bioRxiv · 10.1101/2021.05.14.444203

Dissection of N-, O- and glycosphingolipid glycosylation changes in PaTu-S pancreatic adenocarcinoma cells upon TGF-β challenge

Zhang, J.·Zhang, Z.·Holst, S.·BlÖchl, C.·Madunic, K.·Wuhrer, M.·ten Dijke, P.·Zhang, T.
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-{beta} (TGF-{beta}) plays a key role in tumor progression, which is often associated with aberrant glycosylation. How PDAC cells respond to TGF-{beta} and the role of glycosylation therein is, however, not well known. Here, we investigated the TGF-{beta}-mediated response and glycosylation changes in SMAD4-deficient PaTu-8955S (PaTu-S) cell line. PaTu-S cells responded to TGF-{beta} by upregulating SMAD2 phosphorylation and target gene expression. TGF-{beta} induced expression of the mesenchymal marker N-cadherin, but did not significantly affect epithelial marker E-cadherin expression. The differences of N-glycans, O-glycans and glycosphingolipid (GSL) glycans in PaTu-S cells with TGF-{beta} stimulation were examined. TGF-{beta} treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in line with TGF-{beta}-induced changes in the expression of glycosylation-related genes. In addition, we observed differences in O- and GSL-glycosylation profiles after TGF-{beta} treatment, including lower levels of sialylated Tn antigen, and neoexpression of globosides. Furthermore, SOX4 expression was upregulated upon TGF-{beta} stimulation, and its depletion blocked the TGF-{beta}-induced N-glycomic changes. Thus, our study provides a mechanism by which TGF-{beta}-induced N-glycosylation changes in SOX4 dependent and SMAD4 independent manner in pancreatic cancer cells. Our results open up avenues to study the relevance of glycosylation in TGF-{beta} signaling in SMAD4 inactivated PDAC.

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Zhang, J., Zhang, Z., Holst, S., BlÖchl, C., Madunic, K., Wuhrer, M., ten Dijke, P., Zhang, T.. 2021-05-17. Dissection of N-, O- and glycosphingolipid glycosylation changes in PaTu-S pancreatic adenocarcinoma cells upon TGF-β challenge. https://doi.org/10.1101/2021.05.14.444203

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