Metastasis accounts for more than 90 percent of cancer related deaths, yet effective therapeutics for metastatic cancer is lacking. Our long term goals are to decipher the molecular and cellular mechanisms underlying cancer metastasis and to explore novel strategies preventing metastatic progression based on mechanistic study.

Project 1: The metabolic role of fascin in cancer metastasis

Our previous work demonstrated fascin as a critical bundling protein driving cancer cell migration and invasion. We demonstrated that pro-metastasis cues in the tumor microenvironment such as TGFß and hypoxia play important roles in fascin overexpression. We went on to solve the crystal structure of fascin, and identified actin binding sites on fascin surface through a structure-guided alanine-scan mutagenesis screening. The results from our lab and others clearly established a role for fascin in the metastatic dissemination of cancer cells. The post-dissemination role of fascin during cancer metastasis is an important and yet under-appreciated area. We recently embarked on a mission to investigate the function of fascin in metastatic colonization and recurrence in non-small cell lung cancer and we discovered a role of fascin in rewiring the cancer metabolism. We are building on these exciting preliminary observations to investigate the metabolic role of fascin in metastatic recurrence. We will further use genetic and pharmacological approaches to explore the feasibility to prevent metastatic recurrence by targeting fascin.

Project 2: Store-operated calcium entry in cancer metastasis

Store-operated calcium entry (SOCE) is a Ca2+ entry mechanism mediated by the ER Ca2+ sensor STIM1 and the plasma membrane channel pore-forming unit Orai1. SOCE is the major Ca2+ entry mechanism in most cancer cells. However, the roles of SOCE in cancer metastasis have not been recognized until recently. We initially reported that STIM1 and Orai1 mediated Ca2+ influx promotes breast cancer cell migration and lung metastasis by facilitating focal adhesion turnover. Since then, the store-operated calcium channels have been implicated in the migration, invasion and progression of various other cancers. More recently we reported that STIM1 and Orai1-mediated oscillatory Ca2+ signals to promote invadopodia formation and melanoma invasion through the non-receptor tyrosine kinase Src. We are cultured cells, xenograft mouse models and genetically engineered mouse models to explore the role of this pathway in melanoma invasion, metastasis and tumor microenvionment.