Candida albicans enhances melanoma cell aggressiveness through p38-MAPK and HIF-1α pathways and metabolic reprogramming

Aparicio-Fernandez, L.; Cazalis-Bereicua, N.; Areitio, M.; Rodriguez-Erenaga, O.; Abio-Dorronsoro, L.; Martin-Souto, L.; Buldain, I.; Marquez, J.; Benedicto, A.; Arteta, B.; Macias-Camara, N.; Gonzalez, M.; Martin Rodriguez, J. E.; Aransay, A. M.; Pellon, A.; Moyes, D. L.; Anguita, J.; Rementeria, A.; Antoran, A.; Ramirez-Garcia, A.

doi:10.1101/2025.01.17.633543

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bioRxiv · 10.1101/2025.01.17.633543

Candida albicans enhances melanoma cell aggressiveness through p38-MAPK and HIF-1α pathways and metabolic reprogramming

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Abstract

Recent studies have increasingly focused on the role of fungi, including Candida albicans, in carcinogenesis. Since C. albicans is a component of the human microbiota, particularly on the skin, we investigated its effect on the phenotype and signalling pathways of melanoma cells. Assays for migration, adhesion, angiogenesis, and hepatic metastasis showed that C. albicans promotes a more malignant phenotype in melanoma cells. At the transcriptomic level, C. albicans increased the expression of VEGF (Vegfa), and genes associated with MAPK and HIF-1 signalling pathways, and with aerobic glycolysis. Further in vitro analysis revealed that TLRs and EphA2 receptors are involved in the recognition of live C. albicans, stimulating VEGF secretion and expression of the AP-1 transcription factor component c-Fos through p38-MAPK and HIF-1. These pathways also regulate the expression of other AP-1 constituents such as Atf3, Jun, and Jund. Moreover, p38-MAPK regulates glycolytic genes like Hk2, Slc2a1, and Eno2. In conclusion, C. albicans activates the p38-MAPK/c-Fos/AP-1 and HIF-1/HIF-1/c-Fos/AP-1 pathways in melanoma cells, promoting a pro-angiogenic environment and metabolic reprogramming. Therefore, this study clarifies the impact of C. albicans on melanoma cells, which can lead to the use of antifungal therapies as complementary to traditional treatments for melanoma.

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Aparicio-Fernandez, L., Cazalis-Bereicua, N., Areitio, M., Rodriguez-Erenaga, O., Abio-Dorronsoro, L., Martin-Souto, L., Buldain, I., Marquez, J., Benedicto, A., Arteta, B., Macias-Camara, N., Gonzalez, M., Martin Rodriguez, J. E., Aransay, A. M., Pellon, A., Moyes, D. L., Anguita, J., Rementeria, A., Antoran, A., Ramirez-Garcia, A.. 2025-01-18. Candida albicans enhances melanoma cell aggressiveness through p38-MAPK and HIF-1α pathways and metabolic reprogramming. https://doi.org/10.1101/2025.01.17.633543

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