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Integrated Transcriptomic and Glycomic Profiling of Glioma Stem Cell Xenografts

Wildburger, Norelle C; Zhou, Shiyue; Zacharias, Lauren G; Kroes, Roger A; Moskal, Joseph R; Schmidt, Mary; Mirzaei, Parvin; Gumin, Joy; Lang, Frederick and Mechref, Yehia, et al. (2015) In Journal of Proteome Research 14(9). p.9-3932
Abstract

Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) have the innate ability to migrate or home toward and engraft in tumors such as glioblastoma (GBM). Because of this unique property of BM-hMSCs, we have explored their use for cell-mediated therapeutic delivery for the advancement of GBM treatment. Extravasation, the process by which blood-borne cells—such as BM-hMSCs—enter the tissue, is a highly complex process but is heavily dependent upon glycosylation for glycan-glycan and glycan-protein adhesion between the cell and endothelium. However, in a translationally significant preclinical glioma stem cell xenograft (GSCX) model of GBM, BM-hMSCs demonstrate unequal tropism toward these tumors. We hypothesized that there may be... (More)

Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) have the innate ability to migrate or home toward and engraft in tumors such as glioblastoma (GBM). Because of this unique property of BM-hMSCs, we have explored their use for cell-mediated therapeutic delivery for the advancement of GBM treatment. Extravasation, the process by which blood-borne cells—such as BM-hMSCs—enter the tissue, is a highly complex process but is heavily dependent upon glycosylation for glycan-glycan and glycan-protein adhesion between the cell and endothelium. However, in a translationally significant preclinical glioma stem cell xenograft (GSCX) model of GBM, BM-hMSCs demonstrate unequal tropism toward these tumors. We hypothesized that there may be differences in the glycan compositions between the GSCXs that elicit homing ("attractors") and those that do not ("non-attractors") that facilitate or impede the engraftment of BM-hMSCs in the tumor. In this study, glycotranscriptomic analysis revealed significant heterogeneity within the attractor phenotype and the enrichment of high mannose type N-glycan biosynthesis in the non-attractor phenotype. Orthogonal validation with topical PNGase F deglycosylation on the tumor regions of xenograft tissue, followed by nLC-ESI-MS, confirmed the presence of increased high mannose type N-glycans in the non-attractors. Additional evidence provided by our glycomic study revealed the prevalence of terminal sialic acid-containing N-glycans in non-attractors and terminal galactose and N-acetyl-glucosamine N-glycans in attractors. Our results provide the first evidence for differential glycomic profiles in attractor and non-attractor GSCXs and extend the scope of molecular determinates in BM-hMSC homing to glioma.

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keywords
Animals, Gene Expression Profiling, Glioma, Glycomics, Glycosylation, Heterografts, Humans, Male, Mannose, Mesenchymal Stromal Cells, Mice, Mice, Nude, Polysaccharides, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
in
Journal of Proteome Research
volume
14
issue
9
pages
8 pages
publisher
The American Chemical Society
external identifiers
  • scopus:84941101536
ISSN
1535-3893
DOI
10.1021/acs.jproteome.5b00549
language
English
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no
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36e5e0d8-05d0-4f9b-83ba-55e4794fa575
date added to LUP
2017-05-16 10:20:50
date last changed
2017-10-22 05:30:35
@article{36e5e0d8-05d0-4f9b-83ba-55e4794fa575,
  abstract     = {<p>Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) have the innate ability to migrate or home toward and engraft in tumors such as glioblastoma (GBM). Because of this unique property of BM-hMSCs, we have explored their use for cell-mediated therapeutic delivery for the advancement of GBM treatment. Extravasation, the process by which blood-borne cells—such as BM-hMSCs—enter the tissue, is a highly complex process but is heavily dependent upon glycosylation for glycan-glycan and glycan-protein adhesion between the cell and endothelium. However, in a translationally significant preclinical glioma stem cell xenograft (GSCX) model of GBM, BM-hMSCs demonstrate unequal tropism toward these tumors. We hypothesized that there may be differences in the glycan compositions between the GSCXs that elicit homing ("attractors") and those that do not ("non-attractors") that facilitate or impede the engraftment of BM-hMSCs in the tumor. In this study, glycotranscriptomic analysis revealed significant heterogeneity within the attractor phenotype and the enrichment of high mannose type N-glycan biosynthesis in the non-attractor phenotype. Orthogonal validation with topical PNGase F deglycosylation on the tumor regions of xenograft tissue, followed by nLC-ESI-MS, confirmed the presence of increased high mannose type N-glycans in the non-attractors. Additional evidence provided by our glycomic study revealed the prevalence of terminal sialic acid-containing N-glycans in non-attractors and terminal galactose and N-acetyl-glucosamine N-glycans in attractors. Our results provide the first evidence for differential glycomic profiles in attractor and non-attractor GSCXs and extend the scope of molecular determinates in BM-hMSC homing to glioma.</p>},
  author       = {Wildburger, Norelle C and Zhou, Shiyue and Zacharias, Lauren G and Kroes, Roger A and Moskal, Joseph R and Schmidt, Mary and Mirzaei, Parvin and Gumin, Joy and Lang, Frederick and Mechref, Yehia and Nilsson, Carol},
  issn         = {1535-3893},
  keyword      = {Animals,Gene Expression Profiling,Glioma,Glycomics,Glycosylation,Heterografts,Humans,Male,Mannose,Mesenchymal Stromal Cells,Mice,Mice, Nude,Polysaccharides,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't,Research Support, U.S. Gov't, Non-P.H.S.},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {9--3932},
  publisher    = {The American Chemical Society},
  series       = {Journal of Proteome Research},
  title        = {Integrated Transcriptomic and Glycomic Profiling of Glioma Stem Cell Xenografts},
  url          = {http://dx.doi.org/10.1021/acs.jproteome.5b00549},
  volume       = {14},
  year         = {2015},
}