BDNF-TrkB-Signaling in Head & Neck Cancer

In Tyrol, 70% of the new HNSCC cases are invasive carcinomas characterized by lymph node involvement. Invasion and metastasis of head and neck squamous cell carcinoma (HNSCC) are tightly related to epithelial-to- mesenchymal transition (EMT) in tumor cells. In our recent work we have proven that EMT is closely bound to the conversion of normal fibroblasts to carcinoma-associated fibroblasts (CAFs) directly at the tumor cells. EMT and CAFs induction result in expression of matrix metalloproteinases (MMPs) both in CAFs and EMT-tumor cells, in activation of MMPs in the pericellular area of the tumor cells and in extracellular matrix (ECM) remodeling. These are major events enabling tumor cells to leave their local microenvironment, to migrate along newly synthesized ECM components and to invade the local tissue, lymph nodes and distant organs. We have been the first to describe the coordinated function of CAFs, which produce brain-derived neurotrophic factor (BDNF), and EMT- transdifferentiated tumor cells, which possess the BDNF receptor: tropomyosin-like kinase B (TrkB). Inflammatory cytokines produced by tumor or stroma cells induce the release of EMT-mediators, as BDNF, in CAFs. The tumor cells in interaction with CAFs have an increased expression of TrkB, which, by subsequent signal pathways, enhance their migration and invasion. The inflammatory cytokines indirectly induce the invasive tumor cell phenotype with the participation of CAFs and with the involvement of the EMT-mediators. The aim of the current application is the mechanistic investigation of the function of the BDNF-TrkB-signaling in regulation of tumor cell invasivity and spreading. This approach understands signal pathways as available targets for therapeutic intervention in highly malignant HNSCC. In our hypothesis the inflammatory cytokine-BDNF- TrkB-axis provides a regulatory backbone for production of matrix tracks in CAFs, which enables the adhesion and migration of tumor cells, and the same axis coordinates the regulation of focal adhesion in tumor cells and triggers them to move along the CAF-produced rails. We will use adhesion, migration and invasion assays, confocal microscopy, and will dissect signaling pathways in order to understand the mechanisms of inflammatory cytokine- BDNF-TrkB-axis -regulated tumor cell invasivity. The proposed project should highlight major therapeutic targets related with the clinically important invasive phenotype of HNSCC.

In the Project P25869-B13, "BDNF TrkB Signaling in Head and neck Cancer " we hypothesized that molecules, so-called neurotrophins, known from the neural system, are released in the tumor cell microenvironment and support the movements of the cancer cells of head and neck cancer. Although these movement induction effects were low in relation to other released factors from the tumor microenvironment as tumor growth factor (TGF-?1), the neurotrophins also provided survival support to cancer cells. The mobility that is induced in cancer cells by microenvironment neurotrophins and by TGF-?1 is a separation of individual cancer cells or cell groups from the tumor cell nest, and also a rapid and oriented escape from the tumor location. This invasion function is combined with improved survival. Both of these effects are attributed to a novel introduced functional unit in the head and neck cancer: the so - called Epithelial Mesenchymal Complex (EMC), which is an executive team of fibroblasts, derived from scar tissue and epithelial tumor cells. The EMC is instrumental in supporting of growth and re-growth of head and neck cancer. The Project P25869-B13 attempted to identify mechanisms which are activated by the EMC and are contributory to therapy resistance, and which must be targeted together with cancer cell related therapies. The Project P25869-B13 enabled the support of scientific career development of several scientists in the Department of Otorhinolaryngology and Head and Neck Surgery in Innsbruck including preparation of one, completion of another habilitation, three complete M. Sc. degrees and one Ph. D. degree. Participants of the Project P25869-B13 presented their results in scientific publications, on national and international congresses, edited a special section in an open access journal and organized an international symposium on the Annual Otorhinolaryngology Congress in 2015, all in context with the project topic.