Project 10

1. Applicant

2. Topic

Comparative analysis of tumor relevant signal transduction proteins in human melanoma and the Xmrk fish melanoma model

3. Short summary

The search for melanoma markers is an ongoing challenge that holds the potential to detect druggable targets. We have previously identified upregulated proteins and genes in either melanoma tissue or mammalian melanocytes expressing the melanoma-causing oncogene xmrk. Among these were transcription factors (FOSL1, EGR1), a phosphatase (DUSP4), secreted and transmembrane proteins (IGFBP3, OPN, TAAL6), and antioxidant enzymes (PRDX2, PRDX6). To elucidate the most interesting candidates, we are using on the one hand well established experimental animal systems, namely Xiphophorus and xmrk-transgenic medaka. On the other hand, we make use of human nevus tissue as well as melanoma tissue and cell lines derived from primary and metastatic melanoma. With these tools, we have now filtered the most promising candidates from the above mentioned list, namely FOSL1 and PRDX6, and have started to examine their function in human melanoma. Similar to the situation in Xmrk-transgenic pigment cells, the transcription factor FOSL1 is induced in a MAPK-dependent manner in human melanoma. FOSL1 induces migration relevant genes such as matrix metalloproteases, enhances migration and is mainly expressed in metastatic melanoma. Currently, we develop dominant negative versions of FOSL1 and its interaction partner JUN to test their function in the fish melanoma model. Furthermore, we will search for new common and exclusive target genes of FOSL1 and JUN in microarrays (collaboration with P3) and for the function of FOSL1 in dissemination tumor cells (collaboration with P6).

With PRDX6, we are investigating a bifunctional protein, whose expression correlates with melanoma malignancy in fish tumors and which is also strongly expressed in human melanoma. Besides the peroxidase, PRDX6 also possesses a phospholipase A2 activity. We found that PRDX6 enhances melanoma proliferation and Cisplatin sensitivity – the latter effect is most likely mediated by the positive influence of PRDX6 on anti-apoptotic AKT signaling. Currently, we are investigating which of the two enzyme activities is required for the effects on proliferation and apoptosis. A second focus of our research is the specific function of the phospholipase A2 activity. Here, we are investigating the role of lipid signaling molecules such as prostaglandins for PRDX6-dependent signaling.

Moreover, the ongoing comparative evaluation of known melanoma markers in fish, mouse and human melanoma will be informative to find the conserved, essential processes in melanoma development. In particular, our xmrk-transgenic medaka provides an excellent tool to validate established melanoma pathways and pathways uncovered by other groups in this network.

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