Project: C03

In depth investigation of the molecular signalling mechanisms and cellular function of midkine, neuropilin-2 and sFLT1 in conjunctival and uveal melanoma

Ocular melanoma is the most frequent cancer entity in the eye in adults and mainly originates in the uveal tract and conjunctiva. Thus, there are plenty of treatment options for primary uveal and conjunctival melanoma, there is urgent need for therapy options for metastatic uveal and conjunctival melanoma. To develop effective therapies, it is of utmost importance to understand the underlying cellular and molecular mechanisms behind metastasis in ocular melanoma. In our preliminary studies, we were able to identify that peritumoral outgrowth of new lymphatics from pre-existing vessels is a decisive risk factor for metastatic spread and a poor prognostic indicator in ocular melanoma. In this course we were also able to detect midkine, a novel player in tumorigenesis of ocular melanoma. Midkine is a key cytokine in tumor-associated lymphangiogenesis, metastasis and immune cell filtration. Extensive analysis of other potential targets has identified two additional important proteins that have potential roles in tumor progression, metastasis, and lymphangiogenesis in ocular melanoma: NRP2 and sFLT1.

In the present project, the characterization of molecular signaling pathways involving midkine will be studied in more detail, by using in vitro and in vivo approaches. Our long-term goal is to be able to translate our findings into clinically used (neo)adjuvant therapeutic strategies in order to improve the recurrence-free and metastasis-free survival rates of ocular melanoma patients.

To carry out this project, the student will employ methods including in vitro and in vivo cancer models, CRISPR-Cas9 technology and pathway analysis, in vitro functional assays and RNA/Protein analysis.