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Centre for Cancer Biomarkers CCBIO

Matrix Biology

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.

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Donald Gullberg in the laboratory.
Photo:
Ingvild Melien

About the group and its research focus

The Gullberg laboratory has characterized the integrin α11β1, which is expressed in subsets of normal fibroblasts and on carcinoma-associated fibroblasts. Cells lacking α11β1 display disturbed cell-collagen interactions, altered metalloproteinase synthesis and reduced cell proliferation. Major projects within the group aim to further understand the role of this collagen receptor and other fibroblast integrins during health and in disease.

The group’s projects

The main focus in the Gullberg lab is firmly anchored in basic science projects. The two major projects in CCBIO have been:

1) Generation and characterization of integrin α11 blocking antibodies;

2) Generation and characterization of α11 promoter -Cre mouse strain.

Project 1): As a first approach to develop blocking, potentially anti-fibrotic reagents, we have developed Mabs against human α11 integrin chain by immunizing NRM mice with recombinant human α11β1. As a result of this project, we have subcloned 25 hybridomas which all are specific for human α11, and out of which three appear to block α11 function. All of the 25 hybridomas react with α11 in fluoresecence activated cell sorting (FACS), work in immunostaining of cryosections and react with α11 in Western blotting.

Project 2): An α11 promoter-driven Cre transgenic mouse strain has successfully been generated. To map the expression pattern and determine if it replicates the endogenous α11 expression, mice have been bred with Credependent lacZ ROSA 26 reporter strain (R26R) (Soriano, 1999). Preliminary data demonstrate that the Cre recombinase is expressed in embryos in an α11-specific pattern.

Research results 

The group’s data based on integrin α11 blocking antibodies has the potential to generate interesting results. Preliminary data from the α11-Cre mouse strain indicate that this transgenic mouse strain might offer a unique opportunity to delete genes in a fibroblast-specific manner and is thus of high general interest the tumor stroma research field.

Plans for the future

For the remainder of the period, the group has three major projects:

1) Continued work with integrin α11 blocking reagents (antibodies and small molecules);

2) Continued work with α11-Cre mouse strain, and

3) Exploring the role of integrin α11 in mouse tumor models.

Project 1): Based on earlier identified α2 integrin modulators, a list of existing small molecules has been selected to be tested for α11 blocking function. Candidate molecules will be tested for their ability to block α11-dependent fibrosis. The fibrosis model relates to Fra-2 transgenic mice as a genetic model for systemic sclerosis. The Fra-2 transgenic mice spontaneously develop skin fibrosis prior to succumbing to the effects of pulmonary fibrosis at 4 months of age. The plan is to start breeding Fra-2 mice in 2017 and to cross these with Itga11-/- mice in 2018. Provided an attenuated fibrosis is seen in this genetic model (Fra-2 tg//α11-/-), α11 inhibitors will be supplied via osmotic pump at different time points in different regimes (early time point before fibrosis has developed as well as starting treatment at later time points when fibrosis has been established) in a manner similar to what has been done in other models.

Project 2): Based on the results with α11-Cre mice, the group will continue a systematic characterization of internal tissues by performing lacZ staining on tissue sections. They also plan to perform skin wounding and bleomycin-induced fibrosis in these mice to analyze α11-driven Cre expression in these pathological conditions including tumor fibrosis.

Project 3): The hypothesis is that α11 regulates collagen assembly in pancreatic ductal adenocarcinoma (PDAC). Pdx1-Cre; KrasG12D mice that develop PDAC with prominent fibrosis will initially be crossed with floxed Itga11 mice (breeding in Bergen since spring 2016) to evaluate possible role of α11 in the prominent collagen production. This project will be performed in collaboration with V.Weaver UCSF.

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."

PubMed Publications