The role of aberrant AKT activation in melanoma growth and metastasis

Melanoma is the most deadly skin malignancy and one of the most rapidly increasing cancers. Like other cancers, melanoma is known to exploit specific signaling pathways for growth and disease progression. The AKT pathway is aberrantly activated in upwards of 70% of melanomas and several lines of clinical evidence suggest that increased AKT signaling plays a role in melanomagenesis. However, in vivo experimental data directly testing the role of aberrant AKT activation in melanoma has been lacking. This dissertation addresses the role of aberrant AKT signaling in melanoma by expressing AKT isoforms and mutant protein in an established non-metastatic mouse model of melanoma. We report that expression of activated AKT1 in the context of BRAFV600E; INK4A/ARFNull melanomas result in highly metastatic disease with lung and brain metastasis. Interestingly, loss of Pten in this same context does not yield significant metastasis but in combination with activated AKT1 results in a significant increase in brain metastasis compared to AKT1 expressing melanomas with wild-type PTEN. Upregulation of mTOR pathway components is observed in AKT1 expressing melanomas compared to PTEN silenced counterparts. Expression of activated AKT3 in the context of BRAFV600E; INK4A/ARFNull melanomas results in significant metastatic disease to the brain while activated AKT2 expression in this same context does not result in observable brain lesions. Lastly, we investigated the role of AKT3E17K in iv melanoma growth and metastasis. We report no observable brain metastases and instead found that in vivo expression of AKT3E17K in BRAFV600E; INK4A/ARFNull melanomas yields highly aggressive lung lesions. In summary, this dissertation furthers our knowledge of melanoma by providing experimental evidence for the role of aberrant AKT signaling in melanoma metastasis to the lungs and brain. Mechanistically, our data reveal that PTEN silencing and AKT1 activation differs in terms of promoting melanoma metastasis, that preferential organspecific metastasis appears to be mediated through specific AKT isoforms, and that the melanoma relevant mutant protein, AKT3E17K, may play a role in promoting lung metastasis. These findings advance our knowledge of melanoma and provide valuable insights for the clinical management of this disease.