Integrated Transcriptomic and Glycomic Profiling of Glioma Stem Cell Xenografts

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• 作者：Norelle C. Wildburger ; Shiyue Zhou ; Lauren G. Zacharias ; Roger A. Kroes ; Joseph R. Moskal ; Mary Schmidt ; Parvin Mirzaei ; Joy Gumin ; Frederick F. Lang ; Yehia Mechref ; Carol L. Nilsson
• 刊名：Journal of Proteome Research
• 出版年：2015
• 出版时间：September 4, 2015
• 年：2015
• 卷：14
• 期：9
• 页码：3932-3939
• 全文大小：418K
• ISSN：1535-3907

文摘

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鈥攕uch as BM-hMSCs鈥攅nter the tissue, is a highly complex process but is heavily dependent upon glycosylation for glycan鈥揼lycan and glycan鈥損rotein 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 (鈥渁ttractors鈥? and those that do not (鈥渘on-attractors鈥? 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鈥揈SI鈥揗S, 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.