Melanoma biology and genetics

Multiple genome-wide association and next-generation sequencing studies have greatly advanced discoveries of melanoma susceptible genotypes. However, only a better understanding of how particular genetic aberrations and genes they affect are implicated in melanoma initiation can help develop novel therapeutic approaches and strategies for disease screening and prevention. This project's main goal was to validate the functional contribution of specific melanoma risk genes to disease penetrance and progression. Few previous studies addressed how some of the newly identified genes functionally influence predisposition to melanoma, yet several genes remained mostly uncharacterized. Extensive functional studies were hampered by the lack of adequate models and materials for investigation. One of the key challenges in investigating the molecular response of melanocytes to UV irradiation and UV-induced melanomagenesis is the lack of appropriate models that accurately represent complex human genotypes. Thus, an additional goal of the project was to develop an experimental model that could address these challenges utilizing advanced technologies, including iPSC and in vivo skin reconstruction. Main findings in the project established that generated iPSC-derived melanocytes retain patients' traits and thus are a suitable model to study novel melanoma genes and disease initiation. Using 3D skin reconstruct models, we showed that melanocytes strongly contribute to the skin's overall UV sensitivity by influencing apoptosis of keratinocytes. Moreover, using this and other models to study a novel melanoma susceptibility gene, MX2, we concluded that it could be regarded as a dual regulator of multiple downstream biological processes in normal melanocyte and melanoma cells. It can exert pleiotropic functions in a cell type and context-dependent manner. We showed that in melanocytes, higher MX2 expression promotes UV sensitivity and thus influences melanoma risk. Contrary, in melanoma tumors, higher MX2 expression is associated with better patient survival. MX2 overexpression in melanoma cells renders them less proliferative and more sensitive to targeted therapy drugs by increasing apoptosis. Furthermore, we identified multiple MX2 downstream targets, including XAF1 involved in fundamental cellular processes such as regulating the cell cycle and mitosis. Finally, we found that MX2 is a crucial factor for the activation of STAT1 and immune response in melanoma. Jointly results acquired in the project will increase our understanding of genetic susceptibility to melanoma and how specific genes and biological pathways contribute to disease development and progression as well as response to therapy. The project has resulted in 3 manuscripts, one published and previously reported, one accepted for publication, and one finalized for submission. These include: Juraleviciute M., Nsengimana J., Newton-Bishop J., Hendriks G. J., and Slipicevic A. “MX2 mediates establishment of interferon response profile, regulates XAF1 and can sensitize melanoma cells to targeted therapy”. Accepted for publication Cancer Medicine Juraleviciute M., Li L., Bra˙ord P., Harland M., O’Shea S., Grigalavicius M., Randerson-Moor J., Newton-Bishop J., Herlyn M., and Slipicevic A. “Dissecting molecular and genetic determinants of UV response using iPSC-based melanocyte model”. Manuscript In addition, results generated during the project have resulted in the successful submission of PhD theses for the PhD candidate working on the project. The results generated in the project have increased general knowledge about melanoma disease biology that can contribute to improved therapy approaches in the future. However, this remains to be developed through additional studies.