Grant: Operating Grant

Metastasis occurs when cancer cells leave the primary tumor and colonize other sites in the body to form new tumors. Over 90% of deaths arising from solid tumors are caused by metastasis. Clinical aspects of metastatic progression are well established. However, changes happening inside a cancer cell - at the molecular level - causing it to become metastatic are poorly understood. Characterizing the molecular basis by which a primary tumor develops the ability to metastasize will help developing more efficient treatments. The loss of certain genes, known as metastasis suppressor genes (MSGs), has been associated with cancer progression. These genes act as a break pedal on cancer cells and stop them from forming tumors throughout the body. However, metastatic cells are using tricks to get rid of these genes, which allow them to establish outside the primary tumor and survive. Melanoma is a skin cancer, which metastasizes very quickly and is often lethal. We recently discovered 22 new genes that suppress melanoma metastasis. Among the novel MSGs identified is the Growth Arrest Specific 1 (Gas1) gene. We have shown that melanoma cells specifically block the expression of Gas1, which allow them to metastasize. Normally, a gene like Gas1 would help the body to kill tumor cells before they become metastatic. Therefore, the loss of Gas 1 creates signals inside the cancer cells that allow them to go through the many changes of becoming metastatic and to survive on their own, outside of the primary tumor. We identified a chemical, SD-208, that can force melanoma metastatic cells to re-express Gas1. Our results suggest SD-208 can block melanoma metastasis. How can metastatic cells block the expression of Gas1? How does Gas1 suppress the metastatic potential of cancer cells? Could SD-208 be used to treat patients with melanoma metastasis? Our research proposes to study these questions with the ultimate goal of developing more efficient anti-metastatic therapies.