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Research in the Marchese lab is directed towards understanding the molecular mechanisms governing G protein-coupled receptor (GPCR) signaling. GPCRs are cell surface receptors expressed throughout the body, mediating a wide variety of physiological processes such as smell, taste, vision, neurotransmission, cardiovascular control, chemotaxis, pain tolerance, immunity and much more. GPCRs are also targets, either directly or indirectly, of a large fraction of medicines prescribed worldwide to treat many diseases. Our goal is to elucidate the mechanisms governing GPCR signaling because we believe it will lead to a better understanding of how GPCR signaling contributes to disease, which may also help to identify new targets that could be used to develop new medicines with less side effects.
Our work is focused primarily on the chemokine receptor CXCR4, a prototypical GPCR implicated in several diseases. Of particular interest to us is the role that CXCR4 signaling plays in cancer progression. CXCR4 is over-expressed on the surface of many types of cancer cells and its expression correlates with poor prognosis. This is mainly because CXCR4 signaling contributes to metastatic disease, the cause of most cancer related deaths. CXCR4 expressing cancer cells tend to disseminate to and colonize anatomical sites where the cognate ligand for CXCR4, called CXCL12, is located. This includes the liver, bone marrow, lungs and lymph nodes among other tissues. Despite the importance of CXCR4 signaling in cancer the mechanisms remain poorly understood.
Current research efforts in the Marchese lab is in two areas. In one area we are focused on elucidating the molecular mechanisms regulating CXCR4 expression in cells. In particular, we are studying how CXCR4 levels are regulated by membrane trafficking within the endocytic pathway. Upon binding to CXCL12 at the cell surface CXCR4 rapidly internalizes and traffics along the endocytic pathway to lysosomes, a terminal degradative compartment. Modification of C-terminal tail lysine residues with ubiquitin by the E3 ubiquitin ligase AIP4 serves as a sorting signal for CXCR4 to enter the lysosomal degradative pathway. Consequently, this leads to a loss in the cellular complement of CXCR4 and long-term attenuation of signaling. Our goal is to understand the mechanisms governing CXCR4 ubiquitination and its sorting into the degradative pathway.
In another area of research, we are studying how CXCR4 signaling contributes to cell migration. CXCR4 expressing cancer cells move up a gradient of CXCL12, its cognate ligand, via a process known as directed cell migration or chemotaxis. This process contributes to tissue colonization and tumor cell metastasis. Our goal is to elucidate the signaling pathways that are responsible for CXCR4-promoted cell migration.
We use cell-free assays, cell culture models and primary cells in our research. We employ state-of-the-art genetic, pharmacological and biochemical approaches. We also use live-cell microscopy imaging to examine CXCR4 trafficking at the subcellular level along the endocytic pathway as well as to monitor cell migration along chemokine gradients using specialized microfluidic devices.