title: Integrated Transcriptomic and Glycomic Profiling of Glioma Stem Cell Xenografts.
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 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.
authors.forename: Norelle C
authors.initials: NC
authors.lastname: Wildburger
authors.affiliation: Department of Chemistry and Biochemistry, Texas Tech University , 2500 Broadway, Lubbock, Texas 79409, United States.
authors.forename: Shiyue
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Chemistry and Biochemistry, Texas Tech University , 2500 Broadway, Lubbock, Texas 79409, United States.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Zacharias
authors.affiliation: The Falk Center for Molecular Therapeutics, McCormick School of Engineering and Applied Sciences, Northwestern University , 1801 Maple Street, Evanston, Illinois 60201, United States.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Kroes
authors.affiliation: The Falk Center for Molecular Therapeutics, McCormick School of Engineering and Applied Sciences, Northwestern University , 1801 Maple Street, Evanston, Illinois 60201, United States.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
authors.affiliation: The Falk Center for Molecular Therapeutics, McCormick School of Engineering and Applied Sciences, Northwestern University , 1801 Maple Street, Evanston, Illinois 60201, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Chemistry and Biochemistry, Texas Tech University , 2500 Broadway, Lubbock, Texas 79409, United States.
authors.forename: Parvin
authors.initials: P
authors.lastname: Mirzaei
authors.affiliation: Department of Neurosurgery and The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center , 1515 Holcombe Boulevard, Houston, Texas 77030, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.affiliation: Department of Neurosurgery and The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center , 1515 Holcombe Boulevard, Houston, Texas 77030, United States.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.affiliation: Department of Chemistry and Biochemistry, Texas Tech University , 2500 Broadway, Lubbock, Texas 79409, United States.
authors.forename: Yehia
authors.initials: Y
authors.lastname: Mechref
authors.forename: Carol L
authors.initials: CL
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods*; D005910:Glioma / Q000378:metabolism*; D054794:Glycomics / Q000379:methods*; D006031:Glycosylation; D064593:Heterografts; D006801:Humans; D008297:Male; D008358:Mannose / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011134:Polysaccharides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011134:Polysaccharides; D008358:Mannose
keywords: N-linked glycosylation; bone marrow-derived human mesenchymal stem cells (BM-hMSCs); glioblastoma; glycomics; high-mannose; sialic acid; transcriptomics