Lance Munn, Ph.D.
Radiation Oncology, Mass General Research Institute
Associate Professor of Radiation Oncology
Harvard Medical School
|PhD Rice University 1993|
The Munn Laboratory focuses on the chemical and mechanical signals responsible for tissue formation, maintenance and disruption. These concepts are central to many normal and patholgical processes, including tumor growth, invasion and metastasis, new blood vessel formation and lymphatic drainage.
Flow of fluid within the lymphatic system is central to many aspects of physiology, including fluid homeostasis and immune function, and poor lymphatic drainage results in significant morbidity in millions of patients each year. We are investigating the mechanisms of lymphatic pumping, considering the nitric oxide and calcium dynamics driven by mechanobiological mechanisms.
Initiation of an immune response requires activation of one or more naïve T cells, which move between lymph nodes searching for matching antigen. If a match is made, the T cell activates, proliferates and enters the circulation in search of the source of antigen. Little is known about this process, especially in the context of anti-cancer immunity and immune checkpoint programs that quench the immune response. We are developing computational models in conjunction with experimental models of immune cell trafficking, lymphatic function and tumor growth to study this problem.
During angiogenesis, endothelial cells abandon their normal arrangement in the vessel wall to migrate into the extravascular matrix. This process is controlled by mul-tiple signals and is necessary for tissue regeneration and tumor growth. Using in vitro models and microfluidic devices, we are investigating the biochemical and mechanical determinants of this morphogenic transformation.
To form new, patent blood vessels, angiogenic sprouts must connect. The process by which this happens -anastomosis – is poorly understood, but represents new targets for vascular therapy. Using intravital microscopy and engineered vascular devices, we are following the steps of anastomosis to identify cellular and molecular mechanisms that may eventually be targeted for enhancing wound healing or inhibiting pathological angiogenesis.
Blood Vessel Remodeling
In many normal physiological responses, endothelial cells and the blood vessel networks they form undergo dramatic changes in morphology and function. Examples include angiogenesis in wound healing, vessel dilation/hyperpermeability in inflammation, and endometrial angiogenesis in the female reproductive cycle.
Endothelial cells, in cooperation with other stromal cells, have to accomplish these diverse changes by responding to a limited number of growth factors including VEGF, PlGF and bFGF. We are using a systems biology approach to understand how the various growth factors and cells cooperate to produce these seemingly diverse functions. Because tumor angiogenesis relies on many of these same growth factors and cellular mechanisms (but in an abnormal, poorly controlled way), these studies will allow a better understanding of tumor angiogenesis and anti-angiogenic therapy.
Cancer Cell Invasion
During the initial stage of metastasis, cancer cells must breach the vessel wall and enter the circulation. Despite intense research in this area, the cellular mechanisms by which this occurs are poorly understood. Some tumors seem to metastasize as single rogue cells, while others travel in groups or clusters; some seem to actively migrate into the vessel, while others may be passively pushed. Using gene array analysis and carefully designed coculture systems, we are assessing the mechanical and cellular determinants of the initiation of metastasis.
Tumor mechanobiology and stress responses
Tumor growth alters the chemical and mechanical environment, exposing cancer cells to many types of stress. We are investigating how mechanical forces and chemical stresses affect tumor mechanobiology and stress granule biology.
With sufficient understanding of the underlying mechanisms, mathematical models can be assembled to validate existing hypotheses and generate new ones.