AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis

Author:

McRee Siobhan K.12ORCID,Bayer Abraham L.34ORCID,Pietruska Jodie2,Tsichlis Philip N.5,Hinds Philip W.12

Affiliation:

1. Program in Genetics, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA

2. Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA

3. Program in Immunology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA

4. Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA

5. Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA

Abstract

Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer due to its highly metastatic nature. Melanomas harboring oncogenic BRAFV600E mutations combined with PTEN loss exhibit unrestrained PI3K/AKT signaling and increased invasiveness. However, the contribution of different AKT isoforms to melanoma initiation, progression, and metastasis has not been comprehensively explored, and questions remain about whether individual isoforms play distinct or redundant roles in each step. We investigate the contribution of individual AKT isoforms to melanoma initiation using a novel mouse model of AKT isoform-specific loss in a murine melanoma model, and we investigate tumor progression, maintenance, and metastasis among a panel of human metastatic melanoma cell lines using AKT isoform-specific knockdown studies. We elucidate that AKT2 is dispensable for primary tumor formation but promotes migration and invasion in vitro and metastatic seeding in vivo, whereas AKT1 is uniquely important for melanoma initiation and cell proliferation. We propose a mechanism whereby the inhibition of AKT2 impairs glycolysis and reduces an EMT-related gene expression signature in PTEN-null BRAF-mutant human melanoma cells to limit metastatic spread. Our data suggest that the elucidation of AKT2-specific functions in metastasis might inform therapeutic strategies to improve treatment options for melanoma patients.

Funder

NSF

Tufts Collaborative Cancer Biology Award

NIH

American Cancer Society

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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