Wainer-Katsir Kerem, Haber Adi, Fishman Hila, Ding Lianghao, Story Michael D, Du Renfei, Kahlert Ulf D, Mannarino Laura, Mirimao Federica, Lupi Monica, D'Incalci Maurizio, Lavy-Shahaf Gitit, Ene Hila, Frechtel-Gerzi Roni, Drawshy Zeina, Martinez-Conde Antonia, Dor-On Eyal, Porat Yaara, Giladi Moshe, Weinberg Uri, Palti Yoram
Novocure LTD, Haifa, Israel.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Cell Death Discov. 2025 Jul 10;11(1):319. doi: 10.1038/s41420-025-02615-5.
Tumor Treating Fields (TTFields) therapy is an approved cancer treatment modality, based on non-invasive application of electric fields to the tumor region. Proteomic and cell biology methods revealed a versatile mechanism of action to be involved in the response to TTFields. In the current research we performed whole transcriptome analysis across tumor types to identify pan-cancer responses to TTFields. For this we collected samples from control and TTFields-treated human cancer cell lines of gastric cancer, pancreatic cancer, ovarian cancer, non-small cell lung carcinoma, pleural mesothelioma, and glioblastoma. The transcriptomic analysis supported previous reported effects: downregulation of pathways associated with cell cycle, cell growth, and proliferation; downregulation of DNA replication and the FA-BRCA DNA repair pathway; and upregulation of cellular responses to stress-senescence, autophagy, and apoptosis. Notably, previously unrecognized downstream effects of TTFields were revealed on cellular metabolism, with downregulation of protein and RNA metabolism, and upregulation of steroid biosynthesis. Additional DNA repair pathways were also found to be downregulated, including nucleotide excision repair, base excision repair, and mismatch repair. In conclusion, this study revealed similar response patterns to TTFields across different tumor types, re-enforcing some already pinpointed mechanisms, while revealing new mechanisms. Unlocking these new mechanisms may allow identification of potential new cancer treatments for application together with TTFields based on mechanistical compatibility.
肿瘤电场疗法（TTFields）是一种已获批准的癌症治疗方式，基于对肿瘤区域无创施加电场。蛋白质组学和细胞生物学方法揭示了其作用机制具有多样性，参与了对TTFields的反应。在当前研究中，我们对多种肿瘤类型进行了全转录组分析，以确定对TTFields的泛癌反应。为此，我们收集了来自胃癌、胰腺癌、卵巢癌、非小细胞肺癌、胸膜间皮瘤和胶质母细胞瘤的对照及经TTFields处理的人癌细胞系的样本。转录组分析支持了先前报道的效应：与细胞周期、细胞生长和增殖相关的通路下调；DNA复制和FA - BRCA DNA修复通路下调；以及细胞对应激衰老、自噬和凋亡的反应上调。值得注意的是，TTFields对细胞代谢的下游效应此前未被认识到，包括蛋白质和RNA代谢下调，以及类固醇生物合成上调。还发现其他DNA修复通路也下调，包括核苷酸切除修复、碱基切除修复和错配修复。总之，本研究揭示了不同肿瘤类型对TTFields的相似反应模式，强化了一些已明确的机制，同时揭示了新机制。解锁这些新机制可能有助于识别基于机制兼容性与TTFields联合应用的潜在新型癌症治疗方法。
