Contact information

Kaisa Lehti,
PhD, Research Director
K. Albin Johansson Senior Cancer Researcher

Haartmaninkatu 8 (PO Box 63)
00014 University of Helsinki

Phone: +358 2941 25034
E-mail: kaisa.lehti (at) helsinki.fi


Affiliations

Research program for Genome Scale Biology


 

Signals and effectors of tissue invasion

In quiescent tissues, cell proliferation and extracellular matrix (ECM) remodeling proceed slowly, cell motility is repressed, and stable cell adhesion is essential for the maintenance and function of the tissue. This situation alters dramatically during tissue injury/repair and pathological disease states such as cancer and vascular disorders, when the cellular signal transduction pathways that enhance cell proliferation, motility and ECM remodeling are activated. In order to engage in tissue invasive functions, tumor cells and activated stromal cells can utilize different molecular strategies depending on their given combinations of cell-type specific traits, genetic alterations, and host connective tissue properties.

Our goal is to contribute to the understanding of both the general principles and unique properties of the context-dependent mechanisms that different types of tumor cells and stromal cells utilize for tissue invasion and remodeling. Our research will be particularly focused on defining how cell signaling, adhesion and cytoskeleton are linked to pericellular proteolysis in a timely and spatially controlled manner to coordinate the key cellular functions. For the identification the dynamic molecular interactions and networks, we are using wide ranges of proteomic and transcriptomic screens as well as biochemical and cell biological assays. Different modes of RTK-dependent tumor cell and vascular cell invasion will be studied both in vivo and in cultured cells within three-dimensional collagen, fibrin or laminin/fibronectin-rich matrices that typify the ECM environment in tumor or surrounding host tissues.

To date, our results have revealed unique interrelated interactions between receptor tyrosine kinases, adhesion receptors, and the membrane-anchored matrix metalloproteinase, MT1-MMP, in both tumor invasion and vessel wall remodeling. By a kinome screen, we have identified FGF receptor-4 and EphA2 as regulators of MT1-MMP-driven cell invasion. Furthermore, we demonstrated that FGFR4 works in a complex with MT1-MMP. A form of FGFR4 associated with poor cancer prognosis (G388R) mediated increased migration signaling through Src and specifically stabilized MT1-MMP in the complexes to enhance collective tumor invasion and EMT in vitro and in vivo. Since FGFR4 is specifically induced in several types of aggressive tumors, the results could help to find means to block the progression of certain tumors.

Our research is funded by the Academy of Finland, University of Helsinki foundations, Association for International Cancer Research, Finnish Cancer Foundations and Magnus Ehrnrooth Foundation.