Loss of Ambra1 promotes melanoma growth and invasion
| Autor: | Marco Carretta, Marco Donia, Daniel H. Madsen, Shawez Khan, Daniela De Zio, Caroline Robert, Jose Javier Bravo-Cordero, Giuseppe Filomeni, Colin J. Daniel, Maria Irene Pires Pacheco, Luca Di Leo, Valérie Bodemeyer, Thomas Sauter, Giuseppina Claps, Francesco Cecconi, Per Guldberg, Fiorella Faienza, Rosalie C. Sears, Julie Di Martino, Salvatore Rizza, Matteo Bordi, Francesca Maria Bosisio, Alex Frias |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male General Physics and Astronomy Adaptor Proteins Signal Transducing/genetics ADHESION Focal Adhesion Kinase 1/metabolism Metastasis Extracellular matrix Mice Multidisciplinaire généralités & autres [F99] [Sciences du vivant] 0302 clinical medicine Cell Movement Melanoma CELL MOTILITY Multidisciplinary biology PROLIFERATION PTEN Phosphohydrolase/genetics Adaptor Proteins CANCER Multidisciplinary Sciences Gene Expression Regulation Neoplastic DIFFERENTIATION Phenotype 030220 oncology & carcinogenesis Science & Technology - Other Topics AUTOPHAGY Beclin-1 Female Autophagy/physiology Signal Transduction Beclin-1/metabolism Proto-Oncogene Proteins B-raf Science INHIBITION Motility PTEN LOSS Multidisciplinary general & others [F99] [Life sciences] General Biochemistry Genetics and Molecular Biology Focal adhesion Melanoma/genetics 03 medical and health sciences Cell Line Tumor Proto-Oncogene Proteins B-raf/genetics medicine EXTRACELLULAR-MATRIX Autophagy PTEN Animals Humans Settore BIO/10 Settore BIO/10 - BIOCHIMICA neoplasms Adaptor Proteins Signal Transducing Cell Proliferation Science & Technology FAK business.industry PTEN Phosphohydrolase Signal Transducing General Chemistry medicine.disease Autophagic Punctum Disease Models Animal 030104 developmental biology Focal Adhesion Kinase 1 Cancer research biology.protein Skin cancer business Transcriptome |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) 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 2021, ' Loss of Ambra1 promotes melanoma growth and invasion ', Nature Communications, vol. 12, 2550 . https://doi.org/10.1038/s41467-021-22772-2 Autophagy 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 2021, ' Loss of Ambra1 promotes melanoma growth and invasion ', Nature Communications, vol. 12, no. 1, 2550, pp. 2550 . https://doi.org/10.1038/s41467-021-22772-2 |
| DOI: | 10.1038/s41467-021-22772-2 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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