Munn Lab Research

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.

Anti-cancer immunity

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.

Tumor Tissue Engineering

Our understanding of cancer progression or response to therapies would benefit from easily accessible, tissue-level assays that recapitulate the biology and anatomy of human tumors. To this end, we have developed methodology for integrating tumor explants with extended stroma and vasculature in vitro. With appropriate culture conditions, a self-assembled vascular network develops and then incorporates into co-cultured tumors excised from mice or patients. Using this approach, we are creating a platform for optimally maintaining samples from patients for the purpose of biological analysis and drug testing.

Lymphatic pumping

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.

Angiogenic sprouting

During angiogenesis, endothelial cells abandon their normal arrangement in the vessel wall to migrate into the extravascular matrix. This process is controlled by multiple 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.

Vascular anastomosis

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.

Mathematical modeling

With sufficient understanding of the underlying mechanisms, mathematical models can be assembled to validate existing hypotheses and generate new ones. 

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Selected Publications (from total of 169)