Distinct fibroblast lineages in skin cancer and disease
Although there is increasing evidence that cancer-associated fibroblasts (CAFs) play an important role in modulating malignant progression, our knowledge about their origin and their phenotypic and functional heterogeneity is limited. We have recently demonstrated that skin dermis arises from two distinct fibroblast lineages, which have different functions during homeostasis and regeneration, and respond differently to signals from neoplastic cells, and thus, it is very likely that these fibroblast lineages play unique roles during epithelial cancer formation and progression and also other skin diseases.
Our aim is to dissect how cancer cells reprogram the gene signature and properties of distinct fibroblast lineages during skin tumour progression in particular in cutaneous SCC and melanoma, and how these specialized cancer-associated fibroblasts alter the microenvironment to promote metastasis.
The molecular basis of melanoma metastasis to Sentinel nodes
Events promoting tumor progression and metastasis occur at early stages of malignant cancers and usually consist of tumor – stromal, tumor - lymph/blood vessel and tumor – immune system interactions. In cutaneous melanoma, lymph node metastasis is the first hallmark of advanced stage disease, thus meaning a worse clinical prognosis with mortality rates exceeding 50%. Identification of leading signaling networks controlling lymphogenic metastasis remains a major challenge. We aim to identify tumor- and stromal-derived factors that influence metastatic behavior and to dissect their signaling and functional properties with regard to enable early lymphogenic tumor spread.
Mesenchymal transition of melanoma
The most dangerous aspect of melanoma is its ability to metastasize. If tumor cells undergo mesenchymal transition, they spread to the lymph nodes and to other parts of the body. At this stage, treatment is complicated and the survival rate is low. The mesenchymal transition (the switch from a non-invasive to an invasive melanoma cell) is driven by a network of different transcription factors which are mainly responsible for the downregulation of adhesion molecules.
Our aim is to find new tools to prevent mesenchymal transition and to identify signal transduction pathways which regulate those adhesion molecules.
Regulation of vascular leak via cingulin
Vascular barrier function is critical for the maintenance of blood flow and tissue homeostasis. In endothelial and epithelial cells the tight junctional complex safeguards this barrier. It comprises transmembrane components, such as claudins, occludin and junctional adhesion molecules (JAMs), as well as a dense plaque of cytosolic tight junction proteins. One of these adaptor molecules is cingulin, which links the tight junction complex to the actin cytoskeleton.
For the first time, we have shown that cingulin is part of the endothelial tight junction complex. We have demonstrated that it regulates claudin-5 mRNA and protein levels and that it plays a role in regulating endothelial permeability. Therefore, the tight junction adaptor protein cingulin and its interaction domains with the cytoskeleton and exchange factors of RhoGTPases could be used to regulate barrier function in endothelial junctions. Consequently this could be a new treatment strategy against vascular leak syndromes.
Prevention of neointima hyperplasia in vascular grafts
The saphenous vein is commonly used for bypassing blocked areas of coronary and carotid arteries. Despite advancements in this field, proliferation of smooth muscle cells below endothelial linings (called intima hyperplasia) remains one of the leading causes of poor long-term outcomes after bypass graft surgery. We plan to analyze the sequence of endothelial and smooth muscle cell activation in vivo and in vitro to define exact mechanisms and we wish to therapeutically interfere with this process.
The morphology of tumor vessels
Anti-angiogenesis has emerged as a new “number 1” in cancer therapy, previously under the idea that preventing angiogenesis starves tumors and cures patients. This did not achieve success. Clinical practice led to a modified concept that anti-angiogenic treatment leads to vessel normalization which improves drug delivery and reduces hypoxia and tumor invasiveness. This raises the question: what is a normalized vessel? Functionally, this means improved blood perfusion, in terms of morphology, this has not been systematically addressed. We wish to perform 3-D reconstructions of normal and tumor vessels and analyze them by laser scan and electron microscopy in regard to endothelial, pericyte, smooth muscle and macrophage interactions. Findings will be correlated with surrogate markers for vascular function. Creating landmarks for identification of ‘pathologic’ versus ‘normalized’ tumor vessel may pre-select for patients or tumor types, who benefit most from anti-angiogenic therapy.