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Updated: Nov 6, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Loss of Ambra1 promotes melanoma growth and invasion
Luca Di Leo1, Valérie Bodemeyer1, Francesca M Bosisio2
1Melanoma Research Team, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
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.
Insights
Activating Molecule in Beclin-1-Regulated Autophagy (Ambra1) acts as a tumor suppressor in melanoma. Its deficiency accelerates tumor growth and metastasis, suggesting FAK1 inhibition as a therapeutic strategy for Ambra1-low melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Melanoma remains a deadly skin cancer with unmet therapeutic needs.
- Understanding melanoma's molecular drivers is crucial for developing new treatments.
Purpose of the Study:
- To investigate the role of Activating Molecule in Beclin-1-Regulated Autophagy (Ambra1) in melanoma development.
- To explore potential therapeutic strategies targeting Ambra1 in melanoma.
Main Methods:
- Utilized Braf/Pten-mutated mouse models of melanoma.
- Assessed tumor growth, survival rates, cell motility, invasion, and epithelial-mesenchymal transition (EMT)-like processes.
- Analyzed extracellular matrix remodeling and focal adhesion kinase 1 (FAK1) signaling pathways.
Main Results:
- Ambra1 deficiency accelerated tumor growth and decreased survival in mouse models.
- Ambra1 deletion promoted melanoma aggressiveness, increasing cell motility, invasion, and EMT.
- Ambra1 deficiency led to altered extracellular matrix and hyperactivated FAK1 signaling.
Conclusions:
- Ambra1 functions as a tumor suppressor in melanoma.
- FAK1 signaling inhibition can reduce melanoma invasion and growth.
- Targeting FAK1 is a potential therapeutic strategy for melanoma with low Ambra1 expression.
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