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The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; Braf\(^{CA}\); Pten\(^{lox/+}\) melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2.
Context
Habitat loss and degradation impose serious threats on biodiversity. However, not all habitats receive the attention commensurate with their ecological importance. Shrub ecotones (successional stages between grasslands and forests) can be highly species-diverse but are often restricted to small areas as prevalent management practices either promote open grassland or forest habitats, threatening the effective conservation of ecotone species.
Objectives
In this study, we assessed the importance of habitat and landscape features of shrub ecotones for the rarely studied true bugs (Heteroptera), a functionally diverse taxon that comprises highly specialized species and broad generalists.
Methods
True bugs were sampled with a beating tray in 118 spatially independent shrub ecotones in a region of 45,000 square kilometers in Germany. In addition to habitat area and landscape context, we used a hedge index to evaluate habitat quality.
Results
Shrub ecotones in open habitats harbored a greater species richness and abundance compared to shaded ones in later seral stages, and species composition differed. Richness and abundance were positively affected by increasing habitat area and quality, whereas an increase in the proportion of semi-natural habitats within 1 km only enhanced richness. While feeding and habitat specialists were more sensitive to habitat area reduction than generalists, this was not the case for weak dispersers and carnivores.
Conclusions
Our findings emphasize the importance of large and high-quality ecotones that form a patchy mosaic of shrubs and herbaceous plants. Such ecotones can benefit both grassland species and species depending on woody plants. Conservation authorities should balance between promoting shrubs and keeping such habitats open to maximize species diversity.