Tumor Treating Fields (TTFields) employ low-intensity, alternating electric fields to exert antitumor activity and have demonstrated efficacy against multiple cancers, including glioblastoma (GBM). Unfortunately, cancer cells inevitably develop resistance to TTFields, highlighting the need to elucidate the underlying mechanisms to develop approaches to induce durable responses. Using a gene network-based machine-learning algorithm, we interrogated TTFields-resistant GBM cells and uncovered a regulatory axis anchored by the prostaglandin E receptor 3 (EP3) and the transcription factor zinc finger 488 (ZNF488). Mechanistically, TTFields induced EP3 upregulation and nuclear envelope localization, where it formed a complex with ZNF488 to induce resistance to TTFields by promoting self-renewal of glioma stem-like cells (GSC). Overexpression of EP3 and/or ZNF488 in TTFields-sensitive GSC conferred resistance and enhanced self-renewal, while expression of non-interacting mutants of these proteins abrogated formation of the nuclear complex and prevented resistance. Inhibition of either partner in this protein complex in resistant GSC, including those freshly isolated from TTFields-resistant GBM tumors, re-sensitized cells to the cytotoxic effects of TTFields, concomitant with reduced self-renewal and in vivo tumorigenicity. Importantly, inhibition of EP3 in TTFields-sensitive GSC preemptively halted the development of resistance. The EP3–ZNF488 axis was significantly upregulated in TTFields-resistant GBM tumors, and co-expression of EP3 and ZNF488 in other cancers correlated with lower survival rates. Collectively, these results indicate that the nuclear EP3–ZNF488 axis is necessary and sufficient to establish TTFields resistance, underscoring the potential to target this axis to prevent or reverse resistance in GBM and possibly other cancers.

中文翻译：

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EP3-ZNF488 轴促进胶质瘤干细胞样细胞的自我更新，以诱导对肿瘤治疗野的耐药性


肿瘤电场治疗 （TTFields） 利用低强度的交变电场来发挥抗肿瘤活性，并已证明对多种癌症有效，包括胶质母细胞瘤 （GBM）。不幸的是，癌细胞不可避免地会产生对 TTFields 的耐药性，这凸显了阐明潜在机制以开发诱导持久反应的方法的必要性。使用基于基因网络的机器学习算法，我们询问了 TTFields 抗性 GBM 细胞，并发现了由前列腺素 E 受体 3 （EP3） 和转录因子锌指 488 （ZNF488） 锚定的调节轴。从机制上讲，TTFields 诱导 EP3 上调和核膜定位，与 ZNF488 形成复合物，通过促进神经胶质瘤干细胞样细胞 （GSC） 的自我更新来诱导对 TTFields 的耐药性。在 TTFields 敏感的 GSC 中过表达 EP3 和/或 ZNF488 可产生耐药性并增强自我更新，而这些蛋白的非相互作用突变体的表达消除了核复合物的形成并阻止了耐药性。在耐药 GSC 中抑制该蛋白质复合物中的任何一方，包括从 TTFields 耐药 GBM 肿瘤中新鲜分离的 GSC，使细胞对 TTFields 的细胞毒作用重新敏感，同时自我更新和体内致瘤性降低。重要的是，在 TTFields 敏感的 GSC 中抑制 EP3 先发制人地阻止了耐药性的发展。EP3-ZNF488 轴在 TTFields 耐药的 GBM 肿瘤中显著上调，EP3 和 ZNF488 在其他癌症中的共表达与较低的生存率相关。 总的来说，这些结果表明，核 EP3-ZNF488 轴对于建立 TTFields 耐药是必要且足够的，强调了靶向该轴以预防或逆转 GBM 和可能的其他癌症耐药的潜力。