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- Title
Truncated O-GalNAc glycans impact on fundamental signaling pathways in pancreatic cancer.
- Authors
Hofmann, Bianca T; Picksak, Aeint-Steffen; Kwiatkowski, Marcel; Grupp, Katharina; Jücker, Manfred; Bachmann, Kai; Mercanoglu, Baris; Izbicki, Jakob R; Kahlert, Christoph; Bockhorn, Maximilian; Güngör, Cenap; Ewald, Florian; Wolters-Eisfeld, Gerrit
- Abstract
Truncated O - N -acetylgalactosamine (O -GalNAc) glycosylation is an important feature of pancreatic ductal adenocarcinoma (PDAC), and the expression of truncated O -GalNAc glycans is strongly associated with decreased survival and poor prognosis. It has been proven that aberrant O -GalNAc glycosylation influences PDAC signaling to promote oncogenic properties, but elucidation of the influence of truncated O -GalNAc glycosylation on different signaling molecules has just been started. We herein elucidated the impact of aberrant O -GalNAc glycosylation on two important PDAC signaling pathways, namely, AKT/mTOR and RAS/MAPK. In PDAC cells expressing truncated O -GalNAc glycans, we identified differentially expressed proteins associated with AKT/mTOR and RAS/MAPK pathways using quantitative proteomics. Since AKT, a key-signaling molecule in PDAC, was among the identified proteins, we analyzed AKT and found a strikingly enhanced S473 phosphorylation and identified a previously unknown O -GalNAc modification. Consecutive analysis of COSMC knockdowns in PDAC revealed strong effects on AKT upstream and downstream effector molecules. Interestingly, truncated O -GalNAc glycans could facilitate an mTORC1 inhibitor resistance using AZD8055. In addition, as AKT/mTOR pathway has extensive cross talks with RAS/MAPK pathway, we analyzed the pathways and found it to be negatively regulated. Finally, we found that the expression of epithelial-mesenchymal transition markers, key features of aggressive PDACs cells, are enhanced and truncated O -GalNAc glycans enhance pancreatic cancer cell growth in a xenograft mouse model. Our study demonstrates that truncated O -GalNAc glycans have a strong impact on AKT/mTOR and RAS/MAPK signaling pathways, are modulated by EGF or IGF-1 signaling and should be considered for targeted therapy of these pathways in PDAC.
- Subjects
PANCREATIC cancer; CELLULAR signal transduction; GLYCANS; CANCER cell growth; PROTEOMICS; PANCREATIC duct; EPITHELIAL-mesenchymal transition
- Publication
Glycobiology, 2024, Vol 34, Issue 6, p1
- ISSN
0959-6658
- Publication type
Article
- DOI
10.1093/glycob/cwab088