Melanoma is the deadliest skin cancer. Despite improvements in the understanding of the molecular mechanisms underlying melanoma biology and in defining new curative strategies, the therapeutic needs for this disease have not yet been fulfilled. Herein, we provide evidence that the Activating Molecule in Beclin-1-Regulated Autophagy (Ambra1) contributes to melanoma development. Indeed, we show that Ambra1 deficiency confers accelerated tumor growth and decreased overall survival in Braf/Pten-mutated mouse models of melanoma. Also, we demonstrate that Ambra1 deletion promotes melanoma aggressiveness and metastasis by increasing cell motility/invasion and activating an EMT-like process. Moreover, we show that Ambra1 deficiency in melanoma impacts extracellular matrix remodeling and induces hyperactivation of the focal adhesion kinase 1 (FAK1) signaling, whose inhibition is able to reduce cell invasion and melanoma growth. Overall, our findings identify a function for AMBRA1 as tumor suppressor in melanoma, proposing FAK1 inhibition as a therapeutic strategy for AMBRA1 low-expressing melanoma. The absence of scaffold protein Ambra1 leads to hyperproliferation and growth in mouse models. Here the authors show that Ambra1 deficiency accelerates melanoma growth and increases metastasis in mouse models of melanoma through FAK1 hyperactivation.

Di Leo, L., Bodemeyer, V., Bosisio, F. M., Claps, G., Carretta, M., Rizza, S., Faienza, F., Frias, A., Khan, S., Bordi, M., Pacheco, M. P., Di Martino, J., Bravo-Cordero, J. J., Daniel, C. J., Sears, R. C., Donia, M., Madsen, D. H., Guldberg, P., Filomeni, G., Sauter, T., Robert, C., De Zio, D., Cecconi, F., Loss of Ambra1 promotes melanoma growth and invasion, <<NATURE COMMUNICATIONS>>, 2021; 12 (1): 2550-2566. [doi:10.1038/s41467-021-22772-2] [https://hdl.handle.net/10807/232487]

Loss of Ambra1 promotes melanoma growth and invasion

Bordi, Matteo;Cecconi, Francesco
Ultimo
2021

Abstract

Melanoma is the deadliest skin cancer. Despite improvements in the understanding of the molecular mechanisms underlying melanoma biology and in defining new curative strategies, the therapeutic needs for this disease have not yet been fulfilled. Herein, we provide evidence that the Activating Molecule in Beclin-1-Regulated Autophagy (Ambra1) contributes to melanoma development. Indeed, we show that Ambra1 deficiency confers accelerated tumor growth and decreased overall survival in Braf/Pten-mutated mouse models of melanoma. Also, we demonstrate that Ambra1 deletion promotes melanoma aggressiveness and metastasis by increasing cell motility/invasion and activating an EMT-like process. Moreover, we show that Ambra1 deficiency in melanoma impacts extracellular matrix remodeling and induces hyperactivation of the focal adhesion kinase 1 (FAK1) signaling, whose inhibition is able to reduce cell invasion and melanoma growth. Overall, our findings identify a function for AMBRA1 as tumor suppressor in melanoma, proposing FAK1 inhibition as a therapeutic strategy for AMBRA1 low-expressing melanoma. The absence of scaffold protein Ambra1 leads to hyperproliferation and growth in mouse models. Here the authors show that Ambra1 deficiency accelerates melanoma growth and increases metastasis in mouse models of melanoma through FAK1 hyperactivation.
2021
Inglese
Di Leo, L., Bodemeyer, V., Bosisio, F. M., Claps, G., Carretta, M., Rizza, S., Faienza, F., Frias, A., Khan, S., Bordi, M., Pacheco, M. P., Di Martino, J., Bravo-Cordero, J. J., Daniel, C. J., Sears, R. C., Donia, M., Madsen, D. H., Guldberg, P., Filomeni, G., Sauter, T., Robert, C., De Zio, D., Cecconi, F., Loss of Ambra1 promotes melanoma growth and invasion, <<NATURE COMMUNICATIONS>>, 2021; 12 (1): 2550-2566. [doi:10.1038/s41467-021-22772-2] [https://hdl.handle.net/10807/232487]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/232487
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