Lance Munn
Associate Prof., Radiation Oncology

Munn Lab Research

Research Projects

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 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.

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. h3. "Click here for Lance Munn's CV":/data/research_statements/6/MunnCV2017.pdf

Current Research

Solid stress and elastic energy as measures of tumour mechanopathology

Solid stress and tissue stiffness affect tumour growth, invasion, metastasis and treatment. Unlike stiffness, which can be precisely  mapped in tumours, the measurement of solid stresses is challenging. Here, we show that two-dimensional spatial mappings of solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and wide size ranges can be obtained via three distinct and quantitative techniques that rely on the measurement of tissue displacement after disruption of the confining structures. Application of these methods in models of primary tumours and metastasis revealed that: (i) solid stress depends on both cancer cells and their microenvironment; (ii) solid stress increases with tumour size; and (iii) mechanical confinement by the surrounding tissue significantly contributes to intratumoural solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to significant discoveries and new therapies.

Nat Biomed Eng. 2016;1:ePub - PMID: 28966873 - PMCID: PMC5621647 - DOI: 10.1038/s41551-016-0004

Fluid forces control endothelial sprouting

 During angiogenesis, endothelial cells (ECs) from intact blood vessels quickly infiltrate avascular regions via vascular sprouting. This process is fundamental to many normal and pathological processes such as wound healing and tumor growth, but its initiation and control are poorly understood. Vascular endothelial cell growth factor (VEGF) can promote vessel dilation and angiogenic sprouting, but given the complex nature of vascular morphogenesis, additional signals are likely necessary to determine, for example, which vessel segments sprout, which dilate, and which remain quiescent. Fluid forces exerted by blood and plasma are prime candidates that might codirect these processes, but it is not known whether VEGF cooperates with mechanical fluid forces to mediate angiogenesis. Using a microfluidic tissue analog of angiogenic sprouting, we found that fluid shear stress, such as exerted by flowing blood, attenuates EC sprouting in a nitric oxide-dependent manner and that interstitial flow, such as produced by extravasating plasma, directs endothelial morphogenesis and sprout formation. Furthermore, positive VEGF gradients initiated sprouting but negative gradients inhibited sprouting, promoting instead sheet-like migration analogous to vessel dilation. These results suggest that ECs integrate signals from fluid forces and local VEGF gradients to achieve such varied goals as vessel dilation and sprouting.

Proc Natl Acad Sci U S A. 2011;108(37):15342-7 - PMID: 21876168 - PMCID: PMC3174629 - DOI: 10.1073/pnas.1105316108

Mechanical compression drives cancer cells toward invasive phenotype

  Uncontrolled growth in a confined space generates mechanical compressive stress within tumors, but little is known about how such stress affects tumor cell behavior. Here we show that compressive stress stimulates migration of mammary carcinoma cells. The enhanced migration is accomplished by a subset of "leader cells" that extend filopodia at the leading edge of the cell sheet. Formation of these leader cells is dependent on cell microorganization and is enhanced by compressive stress. Accompanied by fibronectin deposition and stronger cell-matrix adhesion, the transition to leader-cell phenotype results in stabilization of persistent actomyosin-independent cell extensions and coordinated migration. Our results suggest that compressive stress accumulated during tumor growth can enable coordinated migration of cancer cells by stimulating formation of leader cells and enhancing cell-substrate adhesion. This novel mechanism represents a potential target for the prevention of cancer cell migration and invasion.

Proc Natl Acad Sci U S A. 2011;109(3):911-6 - PMID: 22203958 - PMCID: PMC3271885 - DOI: 10.1073/pnas.1118910109

Munn Lab Careers

Postdoctoral Fellow

Investigator: Munn, Lance
Date Posted: 2017-01-03
Postdoctoral Research position in the Edwin L. Steele Laboratories at Massachusetts General Hospital. The NIH funded project focuses on cancer metastasis and glycocalyx biology. Applicatnts must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. Experience with small animal surgery and intravital microscopy preferred. Applicants should send a C.V., career statement and 3 letters of recommendation to:

Selected Publications (from total of 133)

Munn LL
Cancer and inflammation.
Wiley Interdiscip Rev Syst Biol Med. 2016;9(2):ePub - PMID: 27943646 - PMCID: PMC5561333 - DOI: 10.1002/wsbm.1370
Baish JW, Kunert C, Padera TP, Munn LL
Synchronization and Random Triggering of Lymphatic Vessel Contractions.
PLoS Comput Biol. 2016;12(12):e1005231 - PMID: 27935958 - PMCID: PMC5147819 - DOI: 10.1371/journal.pcbi.1005231
Nia HT, Liu H, Seano G, Datta M, Jones D, Rahbari N, Incio J, Chauhan VP, Jung K, Martin JD, Askoxylakis V, Padera TP, Fukumura D, Boucher Y, Hornicek FJ, Grodzinsky AJ, Baish JW, Munn LL, Jain RK
Solid stress and elastic energy as measures of tumour mechanopathology.
Nat Biomed Eng. 2016;1:ePub - PMID: 28966873 - PMCID: PMC5621647 - DOI: 10.1038/s41551-016-0004
Bazou D, Maimon N, Gruionu G, Munn LL
Self-assembly of vascularized tissue to support tumor explants in vitro.
Integr Biol (Camb). 2016;8(12):1301-1311 - PMID: 27787529 - PMCID: PMC5155578 - DOI: 10.1039/c6ib00108d
Bazou D, Ng MR, Song JW, Chin SM, Maimon N, Munn LL
Flow-induced HDAC1 phosphorylation and nuclear export in angiogenic sprouting.
Sci Rep. 2016;6:34046 - PMID: 27669993 - PMCID: PMC5037418 - DOI: 10.1038/srep34046
Munn LL, Jain RK
The forces of cancer
In: The Scientist. 2016;30(4):ePub
Tse JM, Cheng G, Tyrrell JA, Wilcox-Adelman SA, Boucher Y, Jain RK, Munn LL
Mechanical compression drives cancer cells toward invasive phenotype.
Proc Natl Acad Sci U S A. 2011;109(3):911-6 - PMID: 22203958 - PMCID: PMC3271885 - DOI: 10.1073/pnas.1118910109
Song JW, Munn LL
Fluid forces control endothelial sprouting.
Proc Natl Acad Sci U S A. 2011;108(37):15342-7 - PMID: 21876168 - PMCID: PMC3174629 - DOI: 10.1073/pnas.1105316108
Kamoun WS, Chae SS, Lacorre DA, Tyrrell JA, Mitre M, Gillissen MA, Fukumura D, Jain RK, Munn LL
Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks.
Nat Methods. 2010;7(8):655-60 - PMID: 20581828 - PMCID: PMC2921873 - DOI: 10.1038/nmeth.1475