Research Project

Tissue homeostasis is highly regulated where the extracellular matrix plays multiple and essential roles. If this control is lost severe life threatening diseases can occur such as chronic inflammation, myocarditis, kidney failure and cancer.

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Tumors represent multi-cellular ecosystems where transformed tumorigenic and stromal cells talk to each other and respond to their surrounding specific extracellular matrix that they produce. The extracellular matrix of this tumor bed does not only serve as architectual scaffold but also as reservoir for soluble factors providing mechanical and biochemical information, altogether described by the term « tumor microenvironment ». The tumor microenvironment largely impacts cell behaviour but how is poorly understood. There is ample evidence for the extracellular matrix molecule tenascin-C to regulate tissue maintenance as well as to promote disease malignancy when excessively expressed. The underlying molecular mechanisms how tenascin-C exerts pleiotrophic effects in cancer was difficult to assess due to the lack of relevant in vivo models that appropriately mimic the complexity of cancer tissue. To respond to this challenge, the team has developed several stochastic and autochthonous murine tumor models as well as ex vivo and in vitro models with abundant and no tenascin-C. In particular, the laboratory had developed the first transgenic tumor model with no and high tenascin-C expression that formally demonstrated a pivotal role of tenascin-C in tumor progression (Saupe et al., 2013, Cell Reports). Using state of the art biochemical and cell biological assays, genomics and proteomics as well as tissue imaging we have generated significant mechanistic and molecular insights into the structure – function roles of tenascin-C in cancer progression. The laboratory demonstrated that tenascin-C promotes the angiogenic switch and metastasis. The laboratory further showed that tenascin-C forms fibrillar matrix tracks inside the tumor stroma, serving as niches for tumor and stromal cells. The laboratory further showed that tenascin-C plays a Janus role in tumor angiogenesis with distinct mechanisms promoting and inhibiting blood vessel formation, respectively. Many of these results have prognostic value in cancer diagnosis as e.g. the observation that low tenascin-C levels (which highly exceed tenascin-C levels in normal tissue) is already dangerous because tenascin-C triggers migration and metastasis through a tumor cell intrinsic mechanism (Sun et al., 2018, Cancer Res). Using the novel immune competent tumor models with regulated tenascin-C expression furthermore allowed the team to reveal important roles of tenascin-C in orchestrating tumor immunity. A major goal of the teams reseach is the transfer of knowledge on how the tissue microenvironment impacts cancer progression and chronic inflammation into improving prediction and anti-cancer protocols. We believe that better preclinical models are necessary to recapitulate a relevant tumor microenvironment. Therefore, the development of such models remains a focus of the laboratory.

The Orend-TME-Group
http://jcs.biologists.org/content/joces/129/23/4321.full.pdf
TME Research