Lab Website: https://demali.lab.uiowa.edu/

Molecular Basis of Tumor Cell Metastasis

In order to invade and metastasize cells must lose contact with the underlying basement membrane and neighboring cells. Loss of expression or function of components present in cell-cell or cell-matrix interactions has been found in carcinomas and correlates with poor prognostic outcome in cancer patients. Cells have several mechanisms for linking to their neighbors. These so-called "cell junctions" consist of proteins that assemble into different structures such as gap junctions, tight junctions, adherens junctions, desmosomes and hemidesmosomes, each with specialized functions. Cell-cell junctions of the zonula adherens are prominent in epithelia and are rich in transmembrane adhesive receptors known as cadherins. The cytoplasmic tail of cadherins binds numerous proteins that serve as molecular couplers, linking cell surface adhesion and recognition to both the actin cytoskeleton and cell signaling pathways. A major focus of the work in my lab is to understand cellular mechanisms involved in assembly of cell-cell adhesions and how these linkages become dysregulated to give rise to tumor cell metastasis.

A second focus of my research is to develop methods for targeting adhesion molecules in order to treat metastatic tumor cells. Current therapies aimed at targeting cell adhesion are directed towards modulating the interaction of integrins, the major cell surface adhesion receptors, with the extracellular matrix. However, a complete loss of integrin function can lead to mechanism-based toxicities. An attractive alternative approach is to target integrin associated proteins. We are currently investigating mechanisms for targeting integrin associated proteins and determining if they can increase the sensitivity of melanomas to cancer chemotherapeutics. Through this work we hope to gain a better understanding of the mechanisms underlying tumor cell invasion and metastasis and to lay the foundation for the development of a new class of therapeutics that target cell adhesion.

PubMed link

Department/Program Affiliations:
Biochemistry
Molecular Medicine
MSTP