Melanoma shows preference for early spread through the lymphatic system and metastasis of melanoma to the regional lymph nodes is one of the key indicators of tumor aggressiveness. Despite the paramount importance of lymph node status for the patient outcome, the mechanisms by which melanoma cells are recruited to the lymph nodes are poorly understood. Some of the fundamental questions, such as whether cancer cells in the lymph node directly participate in the formation of distant metastases, remain a subject of controversy. To date, despite the obvious clinical significance, cellular and molecular mechanisms which govern lymphatic metastasis remain poorly understood. Our long-term goal is to understand how the lymphatic system facilitates progression of metastatic disease and to apply that knowledge to develop approaches for prevention and treatment of metastases. Recently, we found that the chemokine receptor CCR8 is expressed in a large subset of malignant melanomas. Its ligand, CCL1 chemokine, is found constitutively expressed mainly on LECs of the lymph node subcapsular sinus (SCS). Inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels, prevented lymph node metastases, and resulted in the formation of large in transit/satellite metastases in the regional lymphatics. Thes studies showed that the signals from the lymph node LECs control tumor cell entry into the lymph node, challenging current paradigm which assumes that the tumor cell entry into the lymph node is passive. Current application builds on this preliminary data to better understand the mechanisms by which melanoma arrives into the lymph nodes as well as to understand the significance of lymph node spread for the formation of distant metastases. Specific objective is to investigate the function of CCR8 on melanoma cells in regional and distant metastases, and to evaluate CCR8 as a therapeutic target for metastatic disease.
Aim1 will employ genetic mouse models and several complementary approaches for inhibition of CCR8 to evaluate its significance for systemic metastasis. Contribution of tumor cells in the lymph node to distant spread will be examined by tracking the fate of metastatic cells from lymph node to distant organs by using photoswitchable fluorescent proteins.
Aim2 will investigate mechanisms of tumor cell entry, travel and exit from the lymphatic vessels by real-time in vivo imaging using multiphoton microscopy. Studies are expected to provide insight into the little understood process of lymphatic metastasis and the cross-talk between the lymphatic endothelial cells and melanoma cells, and to evaluate CCR8 as a potential therapeutic target in melanoma.
These studies are expected to provide insight into the mechanisms by which metastatic melanoma disseminates into the lymph nodes and to distant sites, and to directly assess the contribution of lymph node metastasis to distant metastasis. Furthermore, studies will evaluate chemokine receptor CCR8 as a novel therapeutic target for metastatic melanoma. The knowledge gained from this work is expected to help design novel approaches for treating and preventing melanoma metastases.
|Podgrabinska, Simona; Skobe, Mihaela (2014) Role of lymphatic vasculature in regional and distant metastases. Microvasc Res 95:46-52|