Loss of Ambra1 promotes melanoma growth and invasion

Luca Di Leo, Valérie Bodemeyer, Francesca M. Bosisio, Giuseppina Claps, Marco Carretta, Salvatore Rizza, Fiorella Faienza, Alex Frias, Shawez Khan, Matteo Bordi, Maria P. Pacheco, Julie Di Martino, Jose J. Bravo-Cordero, Colin J. Daniel, Rosalie C. Sears, Marco Donia, Daniel H. Madsen, Per Guldberg, Giuseppe Filomeni, Thomas Sauter, Caroline Robert, Daniela De Zio () and Francesco Cecconi ()
Additional contact information
Luca Di Leo: Melanoma Research Team, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center
Valérie Bodemeyer: Melanoma Research Team, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center
Francesca M. Bosisio: University of Leuven
Giuseppina Claps: INSERM U981, Gustave Roussy Institute
Marco Carretta: Copenhagen University Hospital
Salvatore Rizza: Redox Biology Group, Danish Cancer Society Research Center
Fiorella Faienza: University of Rome Tor Vergata
Alex Frias: Melanoma Research Team, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center
Shawez Khan: Copenhagen University Hospital
Matteo Bordi: Department of Pediatric Hematology and Oncology, Bambino Gesù Children’s Hospital
Maria P. Pacheco: University of Luxembourg
Julie Di Martino: School of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Jose J. Bravo-Cordero: School of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Colin J. Daniel: Department of Molecular and Medical Genetics, Oregon Health & Science University
Rosalie C. Sears: Department of Molecular and Medical Genetics, Oregon Health & Science University
Marco Donia: Copenhagen University Hospital
Daniel H. Madsen: Copenhagen University Hospital
Per Guldberg: Molecular Diagnostics Group, Danish Cancer Society Research Center
Giuseppe Filomeni: Redox Biology Group, Danish Cancer Society Research Center
Thomas Sauter: University of Luxembourg
Caroline Robert: INSERM U981, Gustave Roussy Institute
Daniela De Zio: Melanoma Research Team, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center
Francesco Cecconi: University of Rome Tor Vergata

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22772-2

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