Research Areas

The Gullberg laboratory has characterized the integrin α11β1, which is expressed on subsets of normal fibroblasts and on carcinoma-associated fibroblasts (CAFs) ¹. 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.

Cells are anchored in the extracellular matrix (ECM) via specific receptors belonging to different superfamilies, including the integrin family. Out of the 24 integrin heterodimers, α1β1, α2β1, α10β1 and α11β1 integrins act as primary receptors for native collagens ². ECM, integrins and the fibroblast are increasingly being recognized as being important in the control of the microenvironment ².

The ECM, in addition to its supportive structural role, acts as a reservoir for growth factors, guides cell migration, influences cell signaling, cell growth, cell differentiation and direct angiogenesis. In normal epithelial tissue, the stromal compartment provides the important support for the normal function of the epithelium and other cells constituting an organ. The normal stroma is composed of orderly structured mesenchymal cells (including fibroblasts) and extracellular substances, vascular and lymphatic networks, and minimal immune cell infiltrate. Fibroblasts are cells of mesodermal or ectomesenchymal origin that reside in every tissue of the body. Sampling of fibroblasts from different location in the body has revealed that fibroblasts are characterized by a positional code ³. In addition, rather than being cells of a defined fixed phenotype, they appear to be heterogeneous, even within tissues like skin ⁴. Under certain conditions fibroblasts can be activated and differentiate into so-called myofibroblasts, which are contractile collagen-producing cells. This differentiation occurs during wound healing, fibrosis, and the desmoplastic reaction in the tumor stroma.

The traditional view of the fibroblast as that of a rather passive cell type that merely produces the constituents of the interstitial extracellular matrix, is now changing. This is in part the result from work in the field of tumor biology where a paradigm shift has occurred so that there is now a widespread understanding of the importance of the tumor microenvironment (TME) for tumorigenesis, tumor metastasis and chemoresistance. One of the major cell types that seem to be important for conditioning the microenvironment is the cancer-associated fibroblast (CAF), which like fibroblasts in normal tissues is a heterogeneous population, containing inflammatory subtypes, myofibroblastsic subtypes as well as subtypes characterized by biomarker expression ^{5, 6}. The activated status of many cells in the tumor stroma has been likened to that of a non-healing wound ^{7, 8}. The changes that occur in the stroma during carcinogenesis include induction of fibroblasts proliferation, differentiation into myofibroblasts, altered amount and arrangement of stromal collagen, angiogenesis and increased immune and inflammatory cell infiltrates. Recent studies indicate that such changes in the stroma are not merely a bystander phenomenon, but play major roles in the process of tumorigenmesis ⁷, including tumor cell growth, invasion, metastases, angiogenesis, and chemoresistance ⁹. The detailed mechanisms of these processes, which are likely to be tumor and tissue specific, are however, still largely unknown.

In an effort to develop novel cancer therapeutics, there is currently intensive effort to better understand the dynamic interplay in the TME. Given the central role of the activated CAFs in tumor growth and myofibroblasts in tissue fibrosis, it is of interest to target the fibroblasts in anti-stroma approaches both in tissue and tumor fibrosis. We believe that integrin α11 will be an important biomarker in tissue and tumor fibrosis.

1. Velling, T., Kusche-Gullberg, M., Sejersen, T. & Gullberg, D. cDNA cloning and chromosomal localization of human alpha(11) integrin. A collagen-binding, I domain-containing, beta(1)-associated integrin alpha-chain present in muscle tissues. J Biol Chem 274, 25735-25742 (1999).

2. Zeltz, C. & Gullberg, D. The integrin-collagen connection--a glue for tissue repair? J Cell Sci 129, 653-664 (2016).

3. Chang, H.Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A 99, 12877-12882 (2002).

4. Driskell, R.R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277-281 (2013).

5. Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 214, 579-596 (2017).

6. Costa, A. et al. Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell 33, 463-+ (2018).

7. Dvorak, H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315, 1650-1659 (1986).

8. Dvorak, H.F. Tumors: wounds that do not heal-redux. Cancer Immunol Res 3, 1-11 (2015).

9. Multhaupt, H.A., Leitinger, B., Gullberg, D. & Couchman, J.R. Extracellular matrix component signaling in cancer. Adv Drug Deliv Rev 97, 28-40 (2016).