Associate Investigator Radiation Oncology, Mass General Research Institute

Associate Professor of Radiation Oncology Harvard Medical School

bacterial infections; cancer immunology; cancer progression; lymph; lymph nodes; lymphangiogenesis; lymphatic diseases; lymphatic metastasis; lymphatic system; lymphatic vessels; lymphedema; vascular endothelial growth factor c

Lymphatic vessels are responsible for draining interstitial fluid from tissues and for transporting immune cells to lymph nodes to maintain the body’s immune surveillance. Thus, lymphatics are important in maintaining both tissue fluid balance and proper function of the immune system. Lymphatic vessels also facilitate the dissemination of cancer cells from a primary tumor to regional lymph nodes.

Predictably, disruptions of the lymphatic system lead to lymphedema (accumulation of fluid in tissue that leads to chronic swelling) and the conditions for chronic infections. There are 10 million patients in the US living with lymphedema, a life-long disease for which there is no cure, only symptomatic treatments. In fact, there are no FDA approved drugs indicated to improve lymphatic function. This fact is quite remarkable as the lymphatic system is distributed throughout the entire body—from the meninges of the brain to the tips of the toes—and is involved in many disease processes. Thus, there is a great opportunity to develop the first drugs to improve lymphatic function and in doing so, find treatments for lymphedema that repair the underlying lymphatic dysfunction.

My research group looks to understand the mechanisms behind the growth, maturation and function of lymphatic vessels and how these mechanisms can contribute to the pathogenesis of lymphedema, chronic infections and cancer dissemination. In order to study the role of the lymphatic system in a variety of disease states, we have developed novel animal models which mimic certain aspects of human disease. Further, we have pioneered technologies for intravital lymphatic imaging, where we can follow disease processes and response to therapy longitudinally over time.

Using intravital microscopy, we have investigated the individual steps of lymphatic metastasis. We described the role of functional tumor margin lymphatic vessels in tumor dissemination and the source of lymphatic dysfunction inside tumors. My group has also developed the first chronic lymph node window in a mouse that allows lymph node imaging over the course of weeks. Using this novel model, we have shown that lymph node metastases do not require sprouting angiogenesis for their growth and do not respond to anti-angiogenic therapy. We have also shown that lymph node metastases can further seed distant metastatic sites.

My group has also developed a novel method to study the autonomous contraction of collecting lymphatic vessels in mice. This work opened the door to the wide array of genetic mouse models for studying the underlying functional lymphatic deficits in lymphedema and states of inflammation. Further, we have shown that bacterial infections of the skin can cause long-term disruption of lymphatic function, which makes the tissue prone to reinfection and lymphedema development. Using these models, we hope to make basic research discoveries that lead to the first drugs to improve lymphatic function and treatments for the underlying causes of lymphedema.