Investigating a novel CTRP8-DLK1 interaction and its impact on glioma stemness

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dc.contributor.authorArreza, Leanne
dc.contributor.examiningcommitteeChelikani, Prashen (Oral Biology)en_US
dc.contributor.examiningcommitteeLogue, Susan (Human Anatomy and Cell Science)en_US
dc.contributor.supervisorKlonisch, Thomas
dc.date.accessioned2023-03-16T19:21:39Z
dc.date.available2023-03-16T19:21:39Z
dc.date.copyright2023-03-14
dc.date.issued2023-03-14
dc.date.submitted2023-03-14T20:08:37Zen_US
dc.degree.disciplineHuman Anatomy and Cell Scienceen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractBackground: The C1Q-tumor necrosis factor related protein (CTRP) family has functions in metabolism, immunity, and cancer. Among the CTRP family, CTRP8 remains the least well characterized in terms of function and receptors. In the brain tumor glioblastoma (GBM), CTRP8 impacts migration and treatment resistance through its receptor RXFP1. We investigate a new interaction between CTRP8 and the EGF-like protein Delta-like homolog 1 (DLK1). DLK1 is a well-known regulator of differentiation and is considered a marker of stemness in several cancers. In GBM, elevated DLK1 expression promotes migration, stemness and has been correlated with poor prognosis. There is interest in further understanding complex mechanisms of DLK1 in a cancer context. Methodology: A yeast-two hybrid (Y2H) screen and co-immunoprecipitation (co-IP) were used to characterize CTRP8-DLK1 interaction domains. The U251 cell line was used to assess stemness using tumor sphere formation and glioma stem cell (GSC) marker expression. In the same U251 model we investigate mechanisms responsive to CTRP8-DLK1 that regulate GSCs. Results: The Y2H identified DLK1 as a CTRP8 interaction partner. In co-IP CTRP8 binds full-size DLK1 and a truncated, soluble form of DLK1. DLK1 enhanced sphere formation and GSC marker expression in U251. The pro-stemness effect of DLK1 was counteracted by CTRP8, resulting in an overall reduction in stemness. Reduced stemness in cells expressing a cleavage-resistant DLK1 form revealed potential functions of DLK1 cleavage products as factors regulating the GSC population. In U251 cells expressing DLK1, CTRP8 treatment increased DLK1 intracellular domain (ICD) release and nuclear translocation. DLK1 ICD may act as a transcriptional co-factor revealing a new function for DLK1 ICD. Conclusions: This is the first study describing CTRP8 as a DLK1 ligand. Our findings reveal DLK1 as a promoter of glioma stemness, and CTRP8 as an antagonist. The CTRP8-DLK1 interaction may be part of a novel regulatory system impacting the glioma stem cell niche that can be of clinical relevance.en_US
dc.description.noteMay 2023en_US
dc.description.sponsorshipUniversity of Manitoba Graduate Fellowshipen_US
dc.identifier.urihttp://hdl.handle.net/1993/37210
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectCanceren_US
dc.subjectGliomaen_US
dc.subjectGlioma stem cellsen_US
dc.subjectProtein interactionen_US
dc.subjectCTRP8en_US
dc.subjectDLK1en_US
dc.titleInvestigating a novel CTRP8-DLK1 interaction and its impact on glioma stemnessen_US
dc.typemaster thesisen_US
local.subject.manitobanoen_US
oaire.awardTitleCanada Graduate Scholarship - Master'sen_US
project.funder.identifierhttps://doi.org/10.13039/501100000024en_US
project.funder.nameCanadian Institutes of Health Researchen_US
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