| Description |
Cutaneous melanoma is a highly lethal form of skin cancer with an especially high affinity to spread to the brain relative to other malignancies. Although the cellular and molecular mechanisms that culminate in this devastating complication remain elusive, multiple studies demonstrate a strong link between aberrant PI3K/AKT molecular signaling and melanoma progression, including brain metastasis. At the heart of the PI3K/AKT signaling pathway is the serine/threonine-specific kinase and proto-oncogene, AKT. There are three closely related AKT paralogs (AKT1, AKT2, and AKT3), and mutations that result in constitutive activation of AKT occur at a low frequency in cancer but over a broad range of malignancies, including melanoma. To our knowledge, however, neither the role of different AKT paralogs, nor the effects of different activating mutations in AKT paralogs has been studied in the context of disease progression. This dissertation aims to explore these unanswered questions, and elucidate AKT-induced mechanisms of melanoma progression with an emphasis on brain metastasis. Using a nonmetastatic autochthonous mouse model of melanoma, we expressed three separate constitutively active mutants of each AKT paralog in iv the context of BRAFV600E, Cdkn2a-/-, and Pten-/- tumors. We discovered a mutant-dependent effect on survival for all three AKT paralogs. AKT1E17K emerged as the most deleterious mutation, conferring the lowest mean survival and highest incidence of brain metastasis in mice. Subsequent studies revealed an AKT1E17K-dependent upregulation of focal adhesion factors in primary tumors, in particular phosphorylated FAK (P-FAK), a critical molecular switch that dictates cell motility. A mouse melanoma cell line engineered to express AKT1E17K also exhibited increased P-FAK, in addition to enhanced migration and invasion in functional assays when compared with isogenic parental cells. This phenotype was abrogated by pharmacological inhibition of AKT or FAK. This research contributes valuable knowledge to the field of melanoma biology by identifying AKT1E17K as a potent driver of disease progression and brain metastasis. These studies also highlight FAK as a potential downstream stimulator of the AKT1E17K-induced highly aggressive melanoma phenotype and suggests that AKT and FAK are potential therapeutic targets to diminish brain metastasis. |
