Author(s): Savannah Pettey
Mentor(s): Sheri Holmen
Institution U of U
For the last decade, Utah has had one of the highest incidence rates of melanoma, a cancer that develops in the pigment-producing cells of our skin, known as melanocytes. Melanoma is the deadliest form of skin cancer due to its propensity to metastasize to distant organs, especially the brain. In many advanced melanoma patients, the leading cause of death is brain metastasis. Currently, there are no effective therapies for patients with melanoma brain metastasis, therefore novel treatment strategies are needed to improve patient prognosis. However, we must gain a deeper understanding of the biological mechanisms that drive melanoma progression and metastasis. One of the most frequent signaling pathway alterations in melanoma brain metastases is overactivation of the PI3K/AKT pathway. The PI3K/AKT pathway regulates numerous biological processes, including cell migration and proliferation, apoptosis, transcription, metabolism, and angiogenesis. Hyperactivation of the PI3K/AKT pathway can occur through various mechanisms, the most common involving the loss or deletion of the tumor suppressor gene PTEN. PTEN is the second most commonly mutated tumor suppressor in cancer, and it encodes a phosphatase with dual activity against lipids and proteins. PTEN lipid phosphatase activity is well studied; it directly antagonizes the activity of PI3K by dephosphorylating phosphatidylinositol-3,4,5 triphosphate (PIP3) to form PIP2, which prevents recruitment of AKT to the plasma membrane and suppresses phosphorylation of AKT. A study done by Kircher et al. found that metastatic tumors expressing the activated AKT1 paralog showed enhanced phosphorylation of FAK (P-FAK), suggesting that one possible way that AKT promotes melanoma brain metastasis is by upregulating proteins that play a role in focal adhesions. Although PTEN’s protein phosphatase functions are less understood, it has been found to dephosphorylate the Y397 residue on P-FAK in other cancer types. Additionally, it is known that P_FAK phosphorylates PTEN, which enhances PTEN phosphatase activity and prevents rising levels of intracellular P-FAK. We have observed that PTEN loss cooperates with activated AKT1 to enhance brain metastasis in our melanoma mouse models. This project aims to determine whether this cooperation occurs through loss of PTEN lipid, protein, or non-enzymatic functions. We are utilizing in-vivo mouse models where we introduce mutant forms of PTEN encoding a form of the protein that only exhibits lipid or protein phosphatase activities. We hypothesize that through the mechanisms described above, loss of PTEN lipid and/or protein phosphatase activity will result in sustained FAK phosphorylation, promoting the development of melanoma brain metastases.