ROS-defense and ferroptosis in EMT/plasticity-driven metastatic colonisation

• Applicants: Professor Dr. Thomas Brabletz; Professor Dr. Felix B. Engel
• Subject Area: Pathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566707053

Dissemination and metastatic colonisation of cancer cells in a hostile environment requires a high adaptive-ness. The necessary plasticity of cancer cells is often exerted by a transient and partial activation of the epithelial-mesenchymal transition (EMT)-program, which also confers a high metabolic plasticity. Using the KPC model system for pancreatic cancer, we demonstrated that highly plastic cancer cells with an epithelial phenotype (KPCep) have the highest metastatic capacity, which is almost completely lost in low plasticity cancer cells independent of their phenotype (KPCmes and KPCZ). Thereby KPCep cells are characterized by a high activity of the ROS (reactive oxygen species) protection machinery, including the glutathione (GST) system. This is associated with strong resistance to the ferroptosis cell death pathway, in contrast to the two low metastatic cell types, with a reduced ROS protection and higher ferroptosis sensitivity. We have further demonstrated that the low metastatic cancer cells show reduced expression of factors crucial for synthesis (Gclc, Gss), recycling (Gsr) and target transfer (GstA1, GstA4) of glutathione. Strikingly, we can make use of the high plasticity of KPCep cells, which upon TGF treatment undergo an EMT. This EMT not only confers pro-metastatic properties, but also downregulates expression of the mentioned glutathione enzymes, which is associated with a transient increase of ferroptosis sensitivity. Thus both a stable (in KPCmes) as well as a transient (in TGF treated KPCep) mesenchymal phenotype can be targeted by ferroptosis inducing compounds. In the second funding period we will test the hypothesis, that the plasticity of highly metastatic cancer cells offers a therapeutic window with downregulated ROS protection and increased ferroptosis sensitivity. We will use cell culture, ex vivo and in vivo models to proof this hypothesis and to develop novel therapeutic strategies against highly metastatic cancer (cells).

• DFG Programme: Research Grants