Targeting Wnt/β-catenin-mediated upregulation of oncogenic NLGN3 suppresses cancer stem cells in glioblastoma

• Published in: Cell death & disease Vol. 14; no. 7; p. 423
• Main Authors: Yun, Eun-Jin, Kim, Donghwi, Kim, Sangwoo, Hsieh, Jer-Tsong, Baek, Seung Tae
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.07.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 38/1; 38/109; 38/77; 38/91; 631/67/1922; 631/67/71; 82/29; 82/51; 96; 96/106; 96/31; 96/95; Antibodies; beta Catenin - metabolism; Biochemistry; Biomedical and Life Sciences; Brain cancer; Brain tumors; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Humans; Immunology; Life Sciences; Neoplastic Stem Cells - metabolism; ras GTPase-Activating Proteins - metabolism; Signal transduction; Stem cells; Tumor Microenvironment; Up-Regulation; Wnt protein; Wnt Signaling Pathway; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05967-x

Glioblastoma (GBM) is the most malignant tumor in brain and is highly resistant to therapy. Clinical evidence suggests increased number of cancer stem cells (CSCs) may contribute to the failure of conventional therapies, but the mechanisms associated with acquisition of CSC properties in GBM are not fully understood. We found that DAB2IP suppresses CSC properties by targeting the synaptic proteins neuroligin 3 (NLGN3) in GBM. Furthermore, we showed that GBM-derived NLGN3 has an oncogenic function by inducing CSC properties within GBM. Moreover, elevated NLGN3 transcription mediated by Wnt/β-catenin signaling pathway resulted in increased secretion of NLGN3 into the surrounding tumor microenvironment. Both condition media containing NLGN3 and recombinant NLGN3 transformed neighboring cells to CSCs, suggesting NLGN3 as a critical component inducing CSC properties. Furthermore, targeting NLGN3-bearing CSCs using upstream Wnt/β-catenin inhibitors synergistically enhances the efficacy of conventional treatment. Hence, we unveiled the series of regulatory mechanisms for acquisition of CSC properties in GBM progression by Wnt/β-catenin-mediated NLGN3. These results may provide a new targeting strategy to improve the therapeutic efficacy of GBM treatments.