Lance L. Munn, PhD
Associate Professor of Radiation Oncology
Harvard Medical School
Edwin L. Steele Laboratory for Tumor Biology
As part of the Edwin L. Steele Laboratory for Tumor Biology, research at the Munn Laboratory focuses on blood vessel structure and function in normal and pathological conditions. Within this broad area, I have projects that address:
Leukocyte Trafficking and Blood Dynamics
A physiological inflammatory response requires margination, adhesion and extravasation of leukocytes which then migrate to the region of insult. Some aspects of this process occur in tumors, but in general, the immune response is ineffective. Using mathematical modeling validated by experiments, we have characterized the physical mechanisms that encourage leukocyte adhesion in normal vasculature. These mechanisms are inefficient in tumor vessels due to the abnormal flow conditions and network topology. We are investigating the possibility of altering the fluid dynamics in tumors to encourage infiltration of blood-borne immune cells. Because our tools for studying blood dynamics are fundamentally robust, we can also use them to analyze thrombosis, sickle cells and the mechanics of atherosclerosis.
Heterogenous permeability of tumor vasculature makes it difficult to deliver drugs via systemic injection to all cells in a tumor. The goal of this project is to determine the mechanisms of spatial and organ-specific dependence of vascular leakage in tumors. A better understanding of the mechanisms of barrier modulation will allow the development of strategies for improving drug delivery to all regions of solid tumors.
Cell and Vessel Morphogenesis During Angiogenesis
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 Intravasation
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.
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