The long-term goal of our research is to understand the influence of tumor-microenvironment interactions on the survival and growth of metastatic cells in a distant organ. The interplay between tumor cells and microenvironment has increasingly been recognized as a critical factor during tumor progression, but how it is regulated remains obscure and its therapeutic targeting for cancer treatment is limited. Specifically, our lab studies the impact of a major component of tumor microenvironment, the extracellular matrix (ECM). ECM is formed by large polypeptides that are assembled into highly ordered structures. It serves as a scaffold to support tissue structures and a repertoire of growth factors to regulate cell survival and growth. ECM proteins also directly bind to and signal through adhesion receptors, such as integrins, to modulate cell behavior. The accumulation and crosslinking of ECM is a hallmark of cancer and actively promotes tumor progression via integrin activation.
My laboratory has been investigating the roles of a novel cell surface receptor, GPR56, in metastatic progression, with a focus on its signaling pathway and influence on tumor ECM. GPR56 is a member of the newly described family of G protein-coupled receptors (GPCRs), called adhesion GPCRs (see above figure). Adhesion GPCRs contain seven transmembrane domains that resemble classical GPCRs, but appear to bind to ECM and function as adhesion receptors. These receptors are highly conserved across species and there are 33 of them in human. Many of them were critical regulators during development and diseases and a variety of disorders were observed in the knockout animals. In addition to being a “hybrid” between GPCRs and adhesion receptors, almost all adhesion GPCRs are cleaved into two subunits through a GPS (GPCR Proteolytic Site) motif immediately upstream of their transmembrane domains. These two subunits could attach to each other non-covalently but could also function as independent entities, lending significant complexity to the regulatory mechanisms of adhesion GPCRs. Almost all adhesion GPCRs remain orphan with no well-defined endogenous ligands, creating additional challenge on studying these molecules. Recently, a consortium for adhesion GPCR-related research was formed, and we are honored to be one of its first members.
We discovered that GPR56 inhibits melanoma growth and metastasis and its N-terminus binds to tissue transglutaminase (TG2), a crosslinking enzyme in ECM. These findings led to the speculation that GPR56 regulates melanoma progression through TG2-mediated ECM deposition/crosslinking. We are investigating this further in two fronts:
Through the course of analyzing GPR56 function in melanomas, we established a cellular system to investigate its signaling pathway. Our results proposed that the receptor exists in different activation states. More info...
Melanoma is readily curable when it is at early stages, but becomes deadly once it metastasizes. We predicted that GPR56 inhibits melanoma metastasis via TG2-mediated ECM remodeling. More info...