Stage Master

The tumor microenvironment (TME) plays an important role in cancer either inhibiting or promoting cancer progression. In addition to tumor and stromal cells and soluble factors the TME is composed of a particular extracellular matrix (ECM). An important ECM molecule of the cancer specific TME is tenascin-C. Its high expression correlates with worsened survival in many cancers (Midwood et al., 2016, J Cell Sci). Murine cancer models with abundant and no tenascin-C have revealed that tenascin-C plays multiple roles in cancer such as enhancing tumor cell survival and migration, angiogenesis and metastasis (Saupe et al., 2013, Cell Reports, Langlois et al., 2014, Oncotarget, Rupp et al., 2016, Cell Reports). Tenascin-C can be alternatively spliced, giving rise to more than 400 different molecules. Until today nothing is known which isoform is expressed in cancer tissue and whether different isoforms have different roles in cancer. It is also unknown whether stromal cell and tumor cell derived tenascin-C have similar or different functions. To address these questions we had generated a murine breast cancer model with abundant and no tenascin-C and observed that stromal cell derived tenascin-C plays a role in lung metastasis (Sun et al., in preparation). In contrast, for tumor cell engraftment in an immune competent host both tumor cell derived and stromal tenascin-C are important suggesting that tenascin-C plays a role in tumor immunity. We had generated NGS data from these tumors and want to determine which tenascin-C isoforms are expressed in tumors with tumor cell and stromal cell derived tenascin-C. As we already have identified the characteristics of tumors with stromal and tumor cell derived tenascin-C information about the molecular entity of tenascin-C may shed light on the function of particular isoforms. The M2 master project entails the characterisation of the tenascin-C splice variants in these tumors based on the NGS data and will be done in co-supervision by R. Carapito within the unit. This information is also important to determine the molecular characteristics of the tenascin-C protein in these tumors (collaboration with a proteomics laboratory in Strasbourg (C. Carapito, IPHC)). In addition to alternative splicing the tenascin-C protein can also be modified by gycosylation and citrullination as well as by cleavage that may generate tenascin-C molecules with particular properties (Midwood et al., 2016, J Cell Sci). Altogether, this information is important for the development of a potential future intervention to block tenascin-C activities in cancer.