Department of Biosciences, University of Milan, 20133 Milano, Italy.
Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy.
Int J Mol Sci. 2023 Aug 11;24(16):12673. doi: 10.3390/ijms241612673.
Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by hijacking neuronal mechanisms and interacting with non-neuronal cell types, such as astrocytes and endothelial cells. To enter the interstitial space of the brain parenchyma, GBM cells significantly shrink their volume and extend the invadopodia and lamellipodia by modulating their membrane conductance repertoire. However, the changes in the compartment-specific ionic dynamics involved in this process are still not fully understood. Here, using noninvasive perforated patch-clamp and live imaging approaches on various GBM cell lines during a wound-healing assay, we demonstrate that the sodium-calcium exchanger (NCX) is highly expressed in the lamellipodia compartment, is functionally active during GBM cell migration, and correlates with the overexpression of large conductance K+ channel (BK) potassium channels. Furthermore, a NCX blockade impairs lamellipodia formation and maintenance, as well as GBM cell migration. In conclusion, the functional expression of the NCX in the lamellipodia of GBM cells at the migrating front is a conditio sine qua non for the invasion strategy of these malignant cells and thus represents a potential target for brain tumor treatment.
胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤。其特征是存在高度侵袭性的癌细胞，通过劫持神经元机制并与非神经元细胞类型（如星形胶质细胞和内皮细胞）相互作用，浸润大脑。为了进入脑实质的间质空间，GBM 细胞通过调节其膜电导谱显著缩小其体积并延伸侵袭伪足和片状伪足。然而，这个过程中涉及的特定隔室离子动力学变化仍不完全清楚。在这里，我们使用非侵入性穿孔贴片钳和活细胞成像方法，在各种 GBM 细胞系的划痕愈合测定中，证明钠钙交换器（NCX）在片状伪足隔室中高度表达，在 GBM 细胞迁移过程中具有功能活性，并与大电导钾通道（BK）钾通道的过度表达相关。此外，NCX 阻断会损害片状伪足的形成和维持以及 GBM 细胞的迁移。总之，NCX 在迁移前沿的 GBM 细胞片状伪足中的功能性表达是这些恶性细胞侵袭策略的必要条件，因此代表了脑肿瘤治疗的潜在靶点。
