Our Objectives

Our laboratory studies the coordination between cell-cell adhesion and gene expression, a fundamental process in the formation of multicellular organisms. 

Signaling by cell-cell adhesion is central for cellular and tissue morphogenesis, and alterations in adhesion-mediated signaling are characteristic to the later stages of cancer progression when cancer cells invade into neighboring tissues and metastasize.  We investigate the changes in the coordination between cell adhesion and gene regulation during invasive-metastatic colon cancer development.  

As a model system, we are studying the Wnt/ß-catenin signaling pathway since ß-catenin plays a dual role in the cell: on the one hand it is involved in cell-cell adhesion by linking cadherin cell-cell adhesion receptors to the actin cytoskeleton, and in addition, it can act as the key effector of the Wnt signaling pathway by being a co-transcriptional activator in the nucleus together with TCF.

Beta catenin image

The dual role of ß-catenin in cell-cell adhesion and transcription

Adherens junctions (AJ) assemble via interactions between the extracellular domain of cadherins on adjacent cells. The cytoplasmic domain of cadherins is bound to ß-catenin (ß) or plakoglobin (Pg) that link it to the actin cytoskeleton via α-catenin (α). In the absence of Wnt signaling, cytoplasmic ß-catenin is phosphorylated by a multiprotein complex containing casein kinase I (CKI), glycogen synthase kinase 3ß (GSK), adenomatous polyposis coli (APC) and Axin, which target it for ubiquitination and degradation by the proteasome. Wnt signaling is activated upon binding of the Wnt ligand to the Frizzled (Frz) receptor. This inhibits ß-catenin phosphorylation by GSK, and results in ß-catenin accumulation and its translocation into the nucleus, where it forms a complex with transcription factors of the LEF/TCF family to activate the transcription of various target genes.

The Wnt/ß-catenin pathway is aberrantly activated in over 90% of human colorectal cancer (CRC) patients, and to varying extents in all other types of cancer.  A key question in Wnt/ß-catenin signaling in CRC cancer is the discovery of ß-catenin-TCF target genes that are aberrantly activated during CRC progression and their function in cancer development.  We ask which genes are activated and whether the function of these genes involves conferring an epithelial to mesenchymal transition (EMT) with cancer stem cell properties.

We apply a variety of molecular genetics and cell biological approaches employing genetically modified human CRC cells, mouse models of CRC metastasis to the liver, immunohistochemical and gene array analysis of Wnt/ß-catenin target gene expression in samples of human CRC tissue.  We expect that our studies aimed to unravel the molecular mechanisms involved in CRC invasion and metastasis will provide novel markers for both diagnosis and therapy.