SHH pathway inhibition and astrocyte co-culture induce distinct responses in glioblastoma and cancer stem cells

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dc.contributor.authorKocaturk, Duygu Calik
dc.contributor.authorOzdil, Berrin
dc.contributor.authorAdali, Yasemin
dc.contributor.authorAktug, Huseyin
dc.contributor.authorBozok, Vildan
dc.contributor.authorUysal, Aysegul
dc.date.accessioned2026-09-26T19:18:09Z
dc.date.available2026-09-26T19:18:09Z
dc.date.issued2026
dc.departmentEge Üniversitesi
dc.description.abstractGlioblastoma (GBM) represents an extremely aggressive brain malignancy with limited treatment options, poor prognosis and a highly heterogeneous cellular architecture, including a subpopulation of cancer stem-like cells (CSCs). These CSCs frequently rely on developmental signaling pathways such as Sonic Hedgehog (SHH), which are typically dormant in adult tissue but reactivated in tumors. This study aimed to investigate how SHH pathway inhibition affects both bulk GBM cells (GBMCs) and CD133+ GBM cells (GBM CSCs), with particular emphasis on the influence of astrocyte co-culture, which more closely mimics the brain tumor microenvironment. GBMCs and GBM CSCs were cultured in mono- and astrocyte co-culture systems. They were evaluated through RT-qPCR, immunofluorescence staining, ELISA, TUNEL assay, and cell cycle analysis. By comparing treatment and culture context independently, cyclopamine-mediated SHH inhibition and astrocyte-dependent signals use distinct but interacting effects on cell behavior. Cyclopamine treatment changed SHH pathway activity depending on the cell type and culture condition, whereas astrocyte co-culture regulated GLI1, GLI3, and SUFU expression through a mechanism different from cyclopamine's effect. GBM CSCs exhibited higher SHH secretion in monoculture, which was attenuated under co-culture with cyclopamine. Cell cycle analysis revealed G2/M arrest in GBMCs and G0/G1 arrest in CSCs, with astrocyte co-culture shifting CSCs toward G2/M. Apoptotic gene expression and TUNEL staining indicated enhanced extrinsic apoptosis (via CASP8) in CSCs, further intensified by SHH inhibition and co-culture. Astrocyte co-culture significantly modulates the molecular and phenotypic response of GBM cells to SHH inhibition, reshaping apoptotic and proliferative behaviors in both CSCs and bulk populations. These findings highlight the critical importance of the tumor microenvironment in therapeutic response and suggest that effective targeting of SHH signaling may require models that account for astroglial interactions.
dc.description.sponsorshipTrkiye Bilimsel ve Teknolojik Arascedil;timath;rma Kurumu [117S578] -- This study was carried out by (TUB & Idot;TAK) within the content of the 3001 project with the number 117S578.
dc.identifier.doi10.1038/s41598-026-38199-y
dc.identifier.issn2045-2322
dc.identifier.issue1
dc.identifier.orcid0000-0001-6081-2308
dc.identifier.pmid41654625
dc.identifier.scopus2-s2.0-105031515581
dc.identifier.scopusqualityN/A
dc.identifier.urihttps://doi.org/10.1038/s41598-026-38199-y
dc.identifier.urihttps://hdl.handle.net/11454/135389
dc.identifier.volume16
dc.identifier.wosWOS:001702951600026
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherNature Portfolio
dc.relation.ispartofScientific Reports
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20260922
dc.subjectGlioblastoma (Gbm)
dc.subjectCancer Stem Cells (Cscs)
dc.subjectSonic Hedgehog (Shh) Signaling Pathway
dc.subjectShh Inhibition
dc.subjectAstrocyte
dc.subjectCo-Culture
dc.titleSHH pathway inhibition and astrocyte co-culture induce distinct responses in glioblastoma and cancer stem cells
dc.typeArticle

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