Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• Metastatic dissemination is a complex process involving tumor cell and microenvironment crosstalk.
• Epithelial-mesenchymal transition (EMT) is crucial for metastasis, influencing stemness, drug resistance, and apoptosis.
• Therapeutic targeting of EMT has shown limited success.

Purpose of the Study:

• To identify FDA-approved compounds capable of reversing EMT.
• To investigate the novel role of Teniposide in modulating the EMT program.
• To explore Teniposide's potential as a therapeutic agent against breast cancer metastasis.

Main Methods:

• High-throughput screening of FDA-approved compounds.
• Assessing Teniposide's effect on EMT markers and pathways.
• Evaluating Teniposide's impact on RNA polymerase I (Pol I) activity and rRNA biogenesis.
• Testing Teniposide's efficacy in reducing pulmonary colonization in breast cancer models.

Main Results:

• Teniposide was identified as a potent modulator of EMT, specifically via an IRF7-NMI mediated response.
• Teniposide significantly reduced the expression of the EMT regulator ZEB2.
• Downregulation of ZEB2 by Teniposide inhibited Pol I activity and rRNA biogenesis.
• Teniposide treatment markedly reduced pulmonary colonization of breast cancer cells.

Conclusions:

• Teniposide effectively reverses EMT and mitigates the mesenchymal-like invasive phenotype at low concentrations.
• Teniposide's dual action on EMT and rRNA biogenesis makes it a promising candidate for repurposing.
• Teniposide could be a viable therapeutic option to restrict breast cancer metastasis.