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dc.contributor.advisorPittet, Mikael
dc.contributor.authorSweeney, Jenna Geddes
dc.date.accessioned2019-12-11T11:31:41Z
dash.embargo.terms2019-03-01
dc.date.created2018-03
dc.date.issued2018-01-02
dc.date.submitted2018
dc.identifier.citationSweeney, Jenna Geddes. 2018. Glycan-Mediated Regulation of Melanoma Growth and Survival. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42015619*
dc.description.abstractMalignant transformation and tumor progression are often associated with aberrant glycosylation of cell surface proteins and lipids. Commonly observed changes in glycan composition during malignancy include truncation of serine/threonine O-linked glycans, altered expression of mucins, an increase in overall sialylation and enhanced synthesis of tri- and tetra-antennary complex N-glycans. Increasing evidence supports the idea that the presence of certain glycans correlates with cancer progression, affects tumor cell invasiveness, alters binding to pro-tumorigenic galectins, and promotes metastasis to distant organs. Yet the molecular details underlying how glycans functionally contribute to malignant transformation and progression are poorly understood. From expression-based analyses across multiple cancer lineages, we found that melanomas exhibit significant transcriptional changes in glycosylation-related genes. This glycosylation gene-signature revealed that compared to normal melanocytes, melanomas downregulate the β1,6 N-acetylglucosaminyltransferase, GCNT2, leading to a loss of asparagine(N)-linked I-branched glycans. Moreover, immunohistochemical analyses of clinical melanoma specimens revealed that GCNT2 expression is inversely correlated with progression. Functionally, we found that knockdown of GCNT2/loss of I-branched glycans significantly enhanced melanoma xenograft growth and promoted three-dimensional in vitro melanoma colony formation and survival. Whereas enforced expression of GCNT2/I-branched glycans decreased melanoma xenograft growth and inhibited in vitro colony formation and survival. Mechanistic studies further revealed that GCNT2/I-branched glycans negatively regulated growth factor receptor and adhesion-mediated cell growth and survival, specifically through insulin-like growth factor-1 receptor (IGF1R) and integrin-extracellular matrix mediated signaling pathways. In addition, we found that GCNT2/I-branched glycans reduced ligand binding to IGF1R and fibronectin-binding integrins. In all, our studies expand our current understanding of the role of aberrant glycans in melanoma and how subtle changes in glycan structure can regulate several malignancy-associated pathways to alter melanoma cell signaling, growth and survival.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectglycosylation
dc.subjectcancer
dc.subjectmelanoma
dc.subjectsignaling
dc.subjectsurvival
dc.subjectgrowth
dc.subjectGCNT2
dc.titleGlycan-Mediated Regulation of Melanoma Growth and Survival
dc.typeThesis or Dissertation
dash.depositing.authorSweeney, Jenna Geddes
dash.embargo.until2019-03-01
dc.date.available2019-12-11T11:31:41Z
thesis.degree.date2018
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberDougan, Stephanie
dc.contributor.committeeMemberCummings, Richard
dc.contributor.committeeMemberLang, Deborah
dc.type.materialtext
thesis.degree.departmentMedical Sciences
thesis.degree.departmentMedical Sciences
dash.identifier.vireo
dash.author.emailjennagsweeney@gmail.com


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