Roles of tumor specific extracellular matrix molecule tenascin-C in shaping tumor immunity and promoting angiogenesis and metastasis
PRESENTATION
Short biography of Gertraud Orend
Gertraud Orend had studied Genetics, Biochemistry, Pharmacology and Organic Chemistry in Cologne, Germany, where she did her PhD in the laboratory of Walter Doerfler on epigenetic modifications arising from insertional mutagenesis in Adenovirus type 12-induced hamster tumors. Her observations contributed to the understanding of de novo methylation across the genome, a mechanism that plays an important role in cancer. After obtaining her PhD degree, G. Orend joined the laboratory of Erkki Ruoslahti as postdoctoral fellow at the Burnham Institute in La Jolla, CA, USA where she got interested in the question how cell adhesion regulates cell cycle progression in normal cells and moreover, how this anchorage-dependence is subverted in tumor cells. Then she joined the laboratory of Ruth Chiquet-Ehrismann at the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland, where she investigated signal transduction pathways that are initiated by the interaction of cells with the extracellular matrix molecules fibronectin and tenascin-C, two molecules that are highly expressed in cancer tissue. Then she directed a group at the University of Basel, Switzerland where she continued to work on signal transduction pathways that are induced by cell adhesion to tenascin-C. In 2008 she became lab head of a team at INSERM, U682 and U1109 (MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy) in Strasbourg. She took tenascin-C research to a new level by developing mouse models with defined expression of tenascin-C. Currently, she is group leader in the Institute ImmunoRheumatologie Moléculaire (IRM) in Strasbourg. Her work is focused on the understanding of the roles of tenascin-C in the tumor microenvironment shaping tumor immunity and promoting angiogenesis and metastasis.
Research project
Tumors represent multi-cellular ecosystems where transformed tumorigenic and stromal Tissue homeostasis is highly regulated and if uncontrolled can lead to severe life threatening diseases such as chronic inflammation, myocarditis, kidney failure and cancer. Tumors represent multi-cellular ecosystems where transformed tumorigenic and stromal cells crosstalk to each other and express and respond to their surrounding specific extracellular matrix (ECM) that constitutes the tumor bed. This ECM does not only serve as architectural scaffold but also as reservoir for soluble factors providing mechanical and biochemical information, altogether described by the term « tumor microenvironment » (TME). The TME largely orchestrates cell behavior where the underlying mechanisms are poorly understood. There is ample evidence for the ECM molecule tenascin-C to regulate tissue maintenance as well as to promote disease malignancy, inparticular when tenascin-C is excessively expressed (Midwood et al., 2016, J Cell Sci). The underlying molecular mechanisms how tenascin-C exerts its pleotropic effects in cancer was difficult to assess due to the lack of relevant in vivo models that appropriately mimick complexity of cancer. The Orend goup has developed several stochastic murine tumor models as well as ex vivo and in vitro models with abundant and no tenascin-C expression. Her group 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 as well as tissue imaging Orend and coworkers have generated significant insights into the structure – function relationship of tenascin-C in cancer progression demonstrating that tenascin-C promotes the angiogenic switch and metastasis. The Orend group showed that tenascin-C forms fibrillar matrix tracks, serving as niches for tumor and stromal cells. They further showed that tenascin-C plays a Janus role in tumor angiogenesis with distinct mechanisms that promote and inhibit blood vessel formation, respectively. This Janus activity could explain why tenascin-C increases on one side the abundance of blood vessels in tumors and on the other side promotes blood vessel leakiness. Recently published work from the Orend group also demonstrated that tenascin-C matters as soon as it is expressed in a tumor by promoting tumor cell migration and metastasis (Sun et al., 2017, Cancer Res). Moreover, identified tenascin-C associatd gene expression signatures (e.g. AngioMatrix, YAP-signature) have prognostic value in cancer. Using the novel immune competent tumor models with regulated tenascin-C expression, furthermore allowed to reveal a dual role of tenascin-C in tumor immunity. Understanding the underlying mechanisms and their relevance in cancer prediction and therapy are a major goal of ongoing research.
COLLABORATIONS
The group has established multiple collaborations with national and international scientists as e.g. with K. Midwood (Kennedy Institute of Rheumatology, Oxford, UK), E. van Obberghen-Schilling (iBV, Nice), V. Vogel (ETH, Zürich, Switzerland), R. Kain (AKH, Vienna, Austria), G. Christofori (Uni Basel, Switzerland), K. Schenke-Layland (Tübingen, Germany), V. Orian-Rousseau (KIT, Karlsruhe, Germany), M. de Palma (EPFL, Lausanne, Switzerland), O. Schilling (Freiburg, Germany).
FUNDING
WWorldwide Cancer Research Foundation (WWCR/AICR, 2), ANR-PRCI (3), ANR, INCa (3), ARC (3), Ligue Régional contre le Cancer (6), Ligue National contre le Cancer/INCa, SNF (2), Oncosuisse, KLBB
