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Glutathione-dependent reprogramming in melanoma and its impact on therapy

Subject Area Dermatology
Cell Biology
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 432439324
 
Final Report Year 2025

Final Report Abstract

Cutaneous melanoma (CMM) belongs to the most frequent malignant cancer types in countries of the northern hemisphere. Melanoma therapy is currently based on BRAF/MEK inhibitors (used in CMM patients with BRAFV600E/K mutant melanomas, approximately 50%), and immune checkpoint inhibitors (ICI). Unfortunately, approximately 40-50% of patients do not respond to either therapy or develop resistances, and an improved understanding of mechanisms that prevent therapy success is required. Melanoma cells have a high phenotypic plasticity and can easily reprogram their molecular makeup in order to meet specific demands. This also helps them to withstand therapy pressure. In particular, a low expression of melanocytic differentiation markers and a high expression of pro-invasive/mesenchymal-type genes is associated with resistance to BRAF/MEK inhibitors and ICI. Combination therapies come into the focus of clinicians and pharmaceutical companies to improve established therapies in melanoma. However, certain chemotherapeutic drugs can affect the development of mesenchymal-type sub-populations, possibly impeding therapeutic benefit. In previous studies, we have observed that a reduction of the intracellular antioxidant glutathione, a common event after chemotherapy, caused a phenotypic switch associated with decreased differentiation and increased mesenchymal-type signature. The focus of this project was the identification of the underlying mechanism of phenotypic alterations after glutathione reduction to reveal novel targets in the mesenchymal-type and therapy-resistant tumor cell populations. During our studies, we identified crucial determinants of the glutathione-dependent phenotypic reprogramming. We demonstrated that the two stress-induced transcription factors ATF4 and NRF2 were strongly induced when glutathione was depleted. We revealed that the activation of both transcriptions factors is able to cause a phenotypic switch, which goes along with dedifferentiation and increased migration and invasion. However, this effect was transient, and NRF2 mediated the phenotype even in absence of ATF4, showing that the specific ATF4 programme was not required. In-depth molecular analyses revealed that ATF4 is located upstream of NRF2 and that ATF4 activation led to an obligatory activation sequence that included transcriptional activation of the NRF2 gene (NFE2L2) as well as the glutathione metabolizing gene CHAC1. Consequently, we considered NRF2 as main determinant of the mesenchymal phenotype and proceeded with a stronger focus on NRF2. In a mouse model of melanoma, we showed that NRF2 blocked differentiation and induced the mesenchymal phenotype. Furthermore, the expression of prostaglandin E2 was increased, leading to the suppression of immune infiltration. In summary, the data derived from the project could show that NRF2 is an important mediator of melanoma resilience whose depletion causes a vulnerable cell state.

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