MSc in Biochemistry, University of Copenhagen (2000)
PhD in Cancer Biology, University of Copenhagen (2005)
My research focuses on understanding how innate immune signaling is regulated, and how it impacts on inflammation and cancer. My main interests lie with the function and regulation of the ubiquitin system in these processes, with emphasis on delineating the non-degradative functions of ubiquitin chains.
I studied Biochemistry at the University of Copenhagen and carried out my PhD at the Danish Cancer Society Research Centre on the topic of cell death and cancer. My interest in ubiquitin began as a postdoctoral fellow at the Institute of Cancer Research in London. Here, my colleagues and I discovered that Inhibitor of Apoptosis (IAP) proteins interact with ubiquitin through a conserved ubiquitin-binding module. We demonstrated that this module contributes to the immune regulatory activity of these proteins and that it is important for their oncogenic potential.
As head of my own research team since 2011, I have studied how ubiquitin controls signaling downstream of innate immune receptors such as NOD2 – a bacteria-sensing receptor central for maintaining an immunological barrier in the gastrointestinal tract, and for which loss-of-function mutations predispose to inflammatory bowel disease (IBD), a condition that increases the risk of intestinal cancer. Our work has contributed to understanding the ubiquitin-dependent processes that control NOD2 signaling, including identifying X-linked IAP (XIAP) as an essential ubiquitin ligase for NOD2 signaling. More recently, our work has uncovered that signaling mediated by the linear ubiquitin chain assembly complex (LUBAC), a ubiquitin ligase that mediates signaling by most immune receptors, is regulated by the deubiquitinases OTULIN and SPATA2-CYLD.
In October 2013, I moved to the Ludwig Cancer Research, Oxford Branch to combine our work on the basic concepts of ubiquitin-mediated signaling with the role of these processes in cancer development and progression.
Our research aims to understand how ubiquitin chains contribute to inflammatory signaling triggered in response to infection and by cytokines in the tumour microenvironment. Chronic or unresolved inflammation is an enabling characteristic of cancer and infections are estimated to account for 1 in 6 of all malignancies. Therefore, understanding the basic mechanisms controlling innate immune signalling, will advance our understanding of the interplay between inflammation and cancer, and has the potential to reveal molecular targets for novel treatment strategies.
Ubiquitin can be assembled in eight different ways by the ubiquitin system to create different types of ubiquitin chains that constitute unique signals in the cell: Lys63- and Met1-linked ubiquitin chains, in particularly, play an important role in innate immune signaling and inflammation. Current questions we are addressing include:
• How is the Met1-linked ubiquitin conjugating machinery regulated?
• What is the function of different ubiquitin chains in inflammatory signaling?
• How do ubiquitin chains influence inflammatory responses in the tumor microenvironment?
Ludwig Institute for Cancer Research, Oxford
Nuffield Department of Clinical Medicine
Old Road Campus Research Building
off Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK
T +44 (0) 1865 617507