The role of stromal hyaluronic acid during tumour growth in malignant melanoma

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The stroma of malignant melanoma represents, like in other solid tumours, the benign vicinity of tumour cells. It consists of the stromal tissue with stromal cells (immune cells, fibroblasts, myofibroblasts) and (micro-)vessels being controlled by tumour-derived mediators as well as deposited matrix components and paracrine mediators. Interactions of tumour cells and the stroma decisively influence growth and metastatic behaviour of many solid tumours.Besides the paracrine induction of changes in the extracellular matrix composition, the behaviour of melanoma cells strongly depends on resulting changes of mechanics and network structure of the matrix. The complex convolution of the diverse cues of the stroma currently limits the mechanistic understanding of their specific functions in tumour biology and impede therapeutic approaches. This is especially true for the functional consequences of the induced synthesis of stromal hyaluronic acid (HA) by stromal fibroblasts in several tumour-supporting effects. The collaborative project aims to qualitatively and quantitatively analyse the behaviour of melanoma cells in dependence on the presentation of HA in vitro and in vivo. The project will focus on the HA synthase 2 (HAS2), which was found to be induced in fibroblasts by melanoma cell derived mediators. It is known as the major source of HA in the tumour stroma that is not rescued by other HA synthases in vitro.The synergistic influences of the tumour stroma have to be separated from the specific impacts of stromal HA. This will be accomplished by the in vitro usage of model systems of graded complexity. They consist of decellularised matrices of stimulated fibroblasts with modulated HA synthesis and biomimetic matrices with defined composition, structure and elasticity. The impact of stromal HA on melanoma cell will be characterized in respect to migration, proliferation and gene expression. These in vitro studies will be compared to in vivo studies on tumour growth and metastasis in specifically raised conditional HAS2 knockout mice.As the main result, we will answer the question whether the tumour-supporting effects of the induced HA synthesis in the tumour-associated stroma can be directly related to the HAS2 based occurrence of HA in the stroma. By that we will find out, whether HAS2-related processes might represent putative anti-proliferative and -metastatic targets in melanoma therapy.