Professor Donald Gullberg has his background in medical chemistry from Uppsala University, and has been working on collagen receptors and integrin biology. He was recruited to the University of Bergen in 2004 and is now directing the Matrix Biology Group at the Department of Biomedicine.
The research is focused on work related to integrin alpha11 which is a collagen receptor with a number of features making it a key molecule in tissue fibrosis and tumor-stroma interactions. The group has performed detailed molecular studies of cell-collagen interactions. Developed animal models include a constitutive integrin alpha11 knockout mouse model, a transgenic alpha11 promoter reporter strain, and most recently a transgenic mouse strain overexpression of integrin alpha11.
The group’s projects
The CCBIO projects deals with the role of integrin alpha11 in tumor stroma using:
• Tumor-fibroblast heterospheroids as a 3D model system to understand bidirectional communication between tumor cells and fibroblasts.
• Development of new animal models to: 1) block human integrin alpha11 function; 2) conditionally inactivate genes in an integrin alpha11-specific manner.
• In collaboration with Nanotools, the group has generated monoclonal antibodies to human alpha11 integrin which block integrin alpha11 function.
• In collaboration with the transgenic facility at Stanford, a transgenic mouse has been generated where Crerecombinase is driven by 3kb of human integrin alpha11 promoter (ITGA11-Cre mouse v1.0). The long-term aim is to use these models to analyze the role of cancer associated fibroblasts in tumor stroma interactions.
Novel animal models: The first mouse strain enabling conditional inactivation of genes in an integrin alpha11 promoter directed manner has been successfully generated. Characterization of ITGA11-Cre mouse v1.0 is ongoing.
Novel antibodies: Function blocking antibodies as well as antibodies suitable for biomarker studies are being characterized in functional assays as well as immunohistochemistry studies of tissues.
Plans for the future
In addition to ongoing work to characterize alpha11 antibodies and the Cre mouse strain, the group will epitope map alpha11 antibodies using mutant integrin alpha11 variants (with domain swapping and deletions). With regard to the Cre mouse strain they will generate the next generation ITGA11-Cre mouse strain (Itga11- Cre v.2.0) in which the Cre activity is not only restricted to the same tissues as alpha11 expression but also under temporal control. A construct coding for Cre-ERT2 and tdTomato will be introduced in the mouse Itga11 gene (unlike in the existing strain where the group use 3kB of the human ITGA11 gene). The intent is to use it to trace cells expressing alpha11. Another aim is to measure cell dynamics through the fluorescence signal in mice where genes involved in fibrosis or tumor development are conditionally inactivated.
Current challenges in the field
In basic integrin research, major questions concerns a better and more detailed understanding of molecular mechanism of integrin function. This is especially true after recent findings suggesting that collagen-binding integrins do not bind fibrillar forms of collagens in mature tissues in vivo, limiting their role to dynamic situations involving tissue remodeling.
In the field of tumor fibrosis the lack of good fibroblast and myofibroblast biomarkers to better monitor fibroblast heterogeneity in pathology is attracting major attention.
Spring 2016 Interview
Professor Gullberg is directing the Matrix Biology Group at the Department of Biomedicine at UiB. The Gullberg group was the one to discover integrin α11, and they continue to explore the possibilities in this area.
What is the main emphasis of your research?
"We are interested in basic mechanisms of how connective tissue cells interact with the fibrillar protein collagen. In various projects it has become increasingly clear that both wound healing, scarring and solid tumor growth and spread, share some common mechanisms at the molecular level. We currently have funding to pursue projects related to fibrosis (scarring) and the tumor microenvironment (TME)."
Your projects focus on integrin α11, can you tell us more about the significance of this integrin?
"Integrin alpha11 is a collagen receptor that was identified in my laboratory 20 years ago, and amazingly enough it keeps challenging us as we try to understand what it does. We have learned some basic things about this receptor in the time that we have been acquainted. It mediates cell adhesion and cell migration on collagen, and it reorganizes collagen to make it more compact. In certain lung tumors it conditions the TME so that tumors grow and spread more."
Can you describe your 2015 researchprojects and your findings?
"Within the framework of CCBIO, two major projects have been pursued in 2015. Firstly, generation and characterization of monoclonal antibodies, Moabs, recognizing human integrin alpha 11 together with a German company, Nanotools. Secondly, generation and characterization of a new transgenic mouse strain with the potential to serve as a tool for conditionally deleting cancer-associated fibroblasts (CAFs) in the stroma of experimental tumors."
Find Gullberg's PubMed publication list here.