Loss of Ambra1 promotes melanoma growth and invasion

Nat Commun. 2021 May 5;12(1):2550. doi: 10.1038/s41467-021-22772-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy / physiology
  • Beclin-1 / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Models, Animal
  • Female
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Melanoma / genetics*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phenotype
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Signal Transduction
  • Transcriptome

Substances

  • AMBRA1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Ambra1 protein, mouse
  • Beclin-1
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse