The transcriptomic fingerprint of cancer response to Tumor Treating Fields (TTFields)

Our plain-English summary of The transcriptomic fingerprint of cancer response to Tumor Treating Fields (TTFields), by K. Wainer-Katsir, A. Haber, H. Fishman, et al (Cell Death Discovery, 2025).

The study

• Authors: K. Wainer-Katsir, A. Haber, H. Fishman, L. Ding, M.D. Story, R. Du, U.D. Kahlert, L. Mannarino, F. Mirimao, M. Lupi, M. D'Incalci, G. Lavy-Shahaf, H. Ene, R. Frechtel-Gerzi, Z. Drawshy, A. Martinez-Conde, E. Dor-On, Y. Porat, M. Giladi, U. Weinberg, Y. Palti
• Journal: Cell Death Discovery
• Published: 2025;11(1):319
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2025. The Author(s).

In plain English

This laboratory study looked at how cancer cells grown in dishes respond to Tumor Treating Fields (TTFields), a cancer treatment that uses electric fields. It did not study asbestos exposure. The authors analyzed gene activity in 16 human cancer cell lines from six tumor types, including two patient-derived pleural mesothelioma lines (CD473 and CD60). They combined previously published and newly generated data. TTFields lowered cell counts compared with untreated cells, by different amounts in different lines. No link to specific driver mutations was established. Across tumor types, genes tied to cell growth and division were turned down, as were most DNA repair pathways. One repair pathway, called NHEJ, was not affected. Stress responses such as senescence and autophagy were turned up. In three lines that were not mesothelioma, cholesterol levels inside the cells rose. The gene pattern resembled that seen with the drug paclitaxel. The authors concluded that TTFields produced similar response patterns across tumor types. They noted that measuring only gene messages (mRNA) can miss other mechanisms, and that studies of isolated cancer cells, which lack immune cells, are limited in detecting immune effects.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study analyzing gene expression (transcriptomics) in cancer cell lines treated or not treated with TTFields, combining previously published and newly generated datasets, with qPCR and lipid measurements to check selected findings
• Who was studied: 16 human cancer cell lines from six tumor types: gastric (AGS, KATOIII), pancreatic (AsPC1, BxPC3), ovarian (OVCAR3), non-small cell lung carcinoma (A549, H1299, H157, H1650, HCC4006), pleural mesothelioma (CD473 and CD60, patient-derived, data collected by Mannarino et al.) and glioblastoma (GBM1, JHH520, NCH644, SF188)
• Exposure: Tumor Treating Fields (alternating electric fields) applied to cells with the inovitro system at frequencies, intensities and durations listed per cell line, compared with untreated control cells; no asbestos or fiber exposure was studied
• Main results:
  • TTFields lowered cell counts relative to untreated controls, with different magnitudes of response in different cell lines
  • A connection between the gene expression changes and specific driver mutations could not be established
  • Gene sets linked to proliferation (MYC targets, E2F targets, G2M checkpoint, mitotic spindle) were downregulated across all datasets
  • Most DNA repair pathways, including BER, NER, MMR and the FA-BRCA pathway, were downregulated over time across tumor types
  • The non-homologous end joining (NHEJ) DNA repair pathway was not affected at any time point
  • Pathways for cellular stress and injury, including senescence, autophagy and CLEAR signaling, were upregulated
  • In A549, AGS and AsPC1 cells treated for 48 hours, cellular cholesterol and most cholesterol esters rose; the most affected ester, CE 18:3, was elevated fourfold
  • The gene response to TTFields correlated highly with that to the antimitotic drug paclitaxel and with various DNA-damaging agents, and was opposite to the response to the PARP inhibitor olaparib
• The authors' conclusion: The authors concluded that the study revealed similar response patterns to TTFields across different tumor types, reinforcing some known mechanisms and revealing new ones
• Limitations the authors state:
  • Transcriptomic analysis measures only mRNA levels, so mechanisms involving protein modification, protein interactions or cellular location (including the antimitotic effect) may be missed
  • Studies on isolated cancer cells lack tissue interplay and immune cells, so they are limited in their ability to identify immune effects (an immune-response signal was seen in the MsigDB analysis but not in the other databases)

Topics

Medical terms in this study, explained in our Lexicon: Tumor Treating Fields (TTFields), Stomach Cancer, Ovarian Cancer, Carcinoma, Pleural Mesothelioma, Apoptosis.

Related studies

• Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models — H. Mumblat, A. Martinez-Conde, et al. (2021)
• Efficacy and immunogenic effects of Tumor Treating Fields (TTFields) in preclinical models of pancreatic ductal adenocarcinoma, with and without gemcitabine/nab-paclitaxel — T. Kan, T. Haj Khalil, et al. (2026)
• Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Acting Dynamics — T. Voloshin, R.S. Schneiderman, et al. (2020)
• Treatment with tumor-treating fields (TTFields) suppresses intercellular tunneling nanotube formation in vitro and upregulates immuno-oncologic biomarkers in vivo in malignant mesothelioma — A. Sarkari, S. Korenfeld, et al. (2023)
• The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy — G. Tanzhu, L. Chen, et al. (2022)
• A review of tumor treating fields (TTFields): advancements in clinical applications and mechanistic insights — X. Li, K. Liu, et al. (2023)

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