The focus of our research is on the role of glycoconjugates in brain and tumor development with a particular emphasis on polysialic acid, a posttranslational modification of mainly the neural cell adhesion molecule NCAM. Work of our lab demonstrated the vital impact of polysialic acid on tumor cell growth, brain development and myelin repair, and revealed possible links between altered polysialic acid synthesis and neurodevelopmental predispositions to schizophrenia and other mental disorders.
We also study the role of other, more recently identified protein carriers of polysialic acid such as SynCAM 1 in oligodendrocyte precursor cells or neuropilin-2 and E-selectin ligand 1 in microglia and macrophages. Major questions arising from findings on the release of polysialic acid by activated microglia are followed up in cell and mouse models lacking either the Siglec receptor recognizing polysialic acid or the polysialyltransferase ST8SIA4, responsible for its biosynthesis in microglia and macrophages.
Furthermore, the production of highly pure polysialic acid with defined chain lengths in a patented process enables us to dissect different biological functions of polysialic acid depending on its degree of polymerization. As a first example, we could define the minimal chain length required to achieve an anti-inflammatory effect of polysialic acid on microglia. By externally adding this type of polysialic acid we were able to show in an in vitro model system that previously destroyed myelin sheaths were almost completely renewed as a result of this anti-inflammatory effect. Future studies will tackle the question if this can also be accomplished in vivo, with the perspective to stimulate the spontaneously occurring but usually incomplete repair of damaged myelin in multiple sclerosis patients.
Another line of our current research explores how polysialic acid and its Siglec receptors modulate the activity of tumor-associated macrophages (TAM). In this realm, we could already demonstrate that interactions between polysialic acid on tumor cells and Siglec-16 on TAM constitute a costimulatory immune checkpoint that improves glioblastoma outcome. Ongoing projects aim at a better understanding of the polysialic acid-induced Siglec-16 signaling and may lead to new strategies for pharmaceutical interventions that can be combined with established immune checkpoint inhibition to improve glioblastoma therapy.