Glycogene expression alterations associated with pancreatic cancer epithelial-mesenchymal transition in complementary model systems.
BACKGROUND
The ability to selectively detect and target cancer cells that have undergone an epithelial-mesenchymal transition (EMT) may lead to improved methods to treat cancers such as pancreatic cancer. The remodeling of cellular glycosylation previously has been associated with cell differentiation and may represent a valuable class of molecular targets for EMT.


RESULTS
As a first step toward investigating the nature of glycosylation alterations in EMT, we characterized the expression of glycan-related genes in three in-vitro model systems that each represented a complementary aspect of pancreatic cancer EMT. These models included: 1) TGFβ-induced EMT, which provided a look at the active transition between states; 2) a panel of 22 pancreatic cancer cell lines, which represented terminal differentiation states of either epithelial-like or mesenchymal-like; and 3) actively-migrating and stationary cells, which provided a look at the mechanism of migration. We analyzed expression data from a list of 587 genes involved in glycosylation (biosynthesis, sugar transport, glycan-binding, etc.) or EMT. Glycogenes were altered at a higher prevalence than all other genes in the first two models (p<0.05 and <0.005, respectively) but not in the migration model. Several functional themes were shared between the induced-EMT model and the cell line panel, including alterations to matrix components and proteoglycans, the sulfation of glycosaminoglycans; mannose receptor family members; initiation of O-glycosylation; and certain forms of sialylation. Protein-level changes were confirmed by Western blot for the mannose receptor MRC2 and the O-glycosylation enzyme GALNT3, and cell-surface sulfation changes were confirmed using Alcian Blue staining.


CONCLUSIONS
Alterations to glycogenes are a major component of cancer EMT and are characterized by changes to matrix components, the sulfation of GAGs, mannose receptors, O-glycosylation, and specific sialylated structures. These results provide leads for targeting aggressive and drug resistant forms of pancreatic cancer cells.
Maupin
Kevin A
KA
Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Sinha
Arkadeep
A
Eugster
Emily
E
Miller
Jeremy
J
Ross
Julianna
J
Paulino
Vincent
V
Keshamouni
Venkateshwar G
VG
Tran
Nhan
N
Berens
Michael
M
Webb
Craig
C
Haab
Brian B
BB
D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D011134:Polysaccharides / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism
D011134:Polysaccharides; D011506:Proteins