POSTECH Biotech Center, POSTECH, Pohang, Republic of Korea.
Department of Life Sciences, POSTECH, Pohang, Republic of Korea.
Cell Death Dis. 2023 Jul 13;14(7):423. 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.
胶质母细胞瘤（GBM）是大脑中最恶性的肿瘤，对治疗具有高度抗性。临床证据表明，癌症干细胞（CSC）数量的增加可能导致常规治疗失败，但与 GBM 中获得 CSC 特性相关的机制尚未完全阐明。我们发现 DAB2IP 通过靶向 GBM 中的突触蛋白神经连接蛋白 3（NLGN3）来抑制 CSC 特性。此外，我们表明，源自 GBM 的 NLGN3 通过在 GBM 内诱导 CSC 特性而具有致癌功能。此外，Wnt/β-catenin 信号通路介导的 NLGN3 转录升高导致 NLGN3 分泌到周围肿瘤微环境中增加。含有 NLGN3 的条件培养基和重组 NLGN3 均可转化邻近细胞为 CSC，表明 NLGN3 是诱导 CSC 特性的关键成分。此外，使用上游 Wnt/β-catenin 抑制剂靶向携带 NLGN3 的 CSC 可协同增强常规治疗的疗效。因此，我们揭示了 Wnt/β-catenin 介导的 NLGN3 诱导 GBM 进展中 CSC 特性获得的一系列调节机制。这些结果可能为提高 GBM 治疗的疗效提供新的靶向策略。
