OxiResist - Consequences and molecular mechanisms of oxidative stress adaptation in squamous cell carcinoma

• Applicant: Dr. Julia Berner
• Subject Area: Dermatology ; Hematology, Oncology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577504881

In cancer, reactive oxygen and nitrogen species (ROS) exert dual functions by acting pro-tumorigenic, promoting tumor pathogenesis and development, or tumor-inhibiting, leading to tumor cell death by irreversible damaging of crucial macromolecules. The processes that are yielded by oxStress are dependent on the balance between ROS and the cell’s antioxidative capacity. An imbalanced redox-homeostasis can result in increased intracellular ROS levels that potentially entail negative effects on tumor cell viability why several anticancer approaches exploit the principal of excessive oxStress induction for cancer cell elimination. Besides, tumor cells usually possess higher intracellular ROS concentrations than healthy counterparts, rendering them more prone to further oxStress insults. However, a higher presence of ROS in cancer cells has also been found to drive tumor progression by modulation of versatile cellular process like cell division and epithelial-to-mesenchymal transition. Furthermore, cancer cells are able to adapt to chronic oxStress, facilitating not only persistence and sustainment of cell growth in challenging environments but also establishment of resistances towards therapeutic approaches. Although ROS are pivotally involved in all stages of tumor pathogenesis, little is known about the consequences and molecular mechanisms of oxStress adaptions, responsible for treatment failures. To improve cancer therapy outcomes, we need to gain fundamental insights into the oxStress resistances in tumors and how to prevent them. The outlined project will address the ROS-resistance mechanisms as major challenge in oncology using 2D and 3D squamous cell carcinoma (SCC) models. Different ROS-tolerant SCC cell lines will be generated by chronic exposure to either H2O2 or HOCl. Since both reactive species are omnipresent in the tumor microenvironment, being remarkably involved in tumor pathogenesis, in-depth characterization of H2O2- and HOCl-tolerant SCC cell lines will allow identification of general oxStress adaption mechanisms. Additionally, we will also test whether resistance towards one single oxidant confers augmented insensitivity towards the other. Comparable, we will as first ever systematically screen for oxStress adaptation-associated cross-resistances towards conventional approaches. As the latter pose an increasing problem in oncological medication by alleviating the efficacy of (combination) anticancer treatments, prediction and identification of potential cross-resistances will enable improved therapy through determination of central resistance pathways. We will employ sophisticated omics-technologies, like RNA sequencing, to detect essential resistance genes, whose functional role and molecular signatures will be verified by CRISPR/Cas knock-down. Ultimately, the impact of target gene knock-down and ROS-resistance on tumor phenotype and treatment response will be validated in the 3D tumor chorioallantois membrane model in ovo.

• DFG Programme: Research Grants