AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis

SIMPLE SUMMARY: Skin cancer, such as melanoma, is often treatable but becomes deadly when it expands to other places in the body, a process called metastasis. While many current drugs target melanoma tumor growth, no drugs yet exist to specifically prevent metastasis. Improving treatment outcomes, therefore, will require an understanding of the molecular mechanisms leading to metastasis. The AKT family of proteins are important regulators of cellular growth and signaling, which play differing roles in cancer. This work sought to study each of the AKT isoforms and their contributions to melanoma cell migration and metastasis. We found that AKT2 specifically regulates melanoma cell metastasis through effects on metabolism and melanoma cell properties, while AKT1 is involved in cellular proliferation and growth. This study suggests that specifically targeting AKT2 and AKT1 represents novel therapeutic strategies for different-stage melanoma patients. ABSTRACT: Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer due to its highly metastatic nature. Melanomas harboring oncogenic BRAF(V600E) 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.