Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically target metastatic disease. Many of the current in vitro models of metastasis focus on the molecular mechanisms of migration, invasion and/or surviving anoikis, but cannot recapitulate the complexity of the environment in which metastasis occurs in vivo. Conversely, in mouse models of metastasis, it has been difficult to examine the molecular mechanisms that enable cells to proceed through each distinct step of metastasis. For these reasons little is known about the challenges facing metastasizing cells in vivo, and how they are overcome. My proposal utilizes a clinically relevant model of melanoma metastasis, patient-derived xenografts in immunocompromised mice, to dissect the metastatic cascade into distinct steps. During the mentored phase of the grant, I will focus on identifying metabolic and stress-response signaling pathways that are specific to melanoma cells at different stages of metastasis, and functionally validate their importance. With these insights, I will continue independent research focusing on the molecular details of the pathways that are engaged during these bottlenecks to identify novel therapeutic targets that may prove useful in treating metastatic disease.
Metastasis is the most lethal aspect of cancer progression, however therapies that specifically target metastatic lesions are nonexistent. This is primarily due to a lack of clinically accurate models of metastatic disease and a poor understanding of the molecular mechanisms that govern each step of the complex cascade of events that comprises metastatic progression. I have used a patient-derived xenogfraft model of late-stage melanoma, which accurately recapitulates the outcome of the disease in the patients, to gain better understanding of the specific barriers that cancer cells must overcome in order to reach distant organs and form metastatic lesions. Using this model, I hope to gain understanding of biology which may be applicable to other types of metastatic cancer, I will gain further insight into the detailed molecular mechanisms that are employed by metastasizing cells and identify potentially novel treatments specific to combating metastatic lesions.
| Piskounova, Elena; Agathocleous, Michalis; Murphy, Malea M et al. (2015) Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527:186-91 |
