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Lance Munn
Deputy Director, Steele Labs
Munn Lab

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. 

 

Lab News

Dr. Munn's WSBM article top cited in 2019
MATH MODELS ADD UP TO IMPROVED CANCER IMMUNOTHERAPY

Normalizing the tumor microenvironment could help powerful immune-enhancing drugs better reach their targets and work more effectively, mathematical models predict

AAAS press release

A framework for advancing our understanding of cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment

Nature Reviews Cancer Article


Selected Publications (from total of 139)

Nikmaneshi MR, Firoozabadi B, Mozafari A, Munn LL
A multi-scale model for determining the effects of pathophysiology and metabolic disorders on tumor growth.
Sci Rep. 2020;10(1):3025 - PMID: 32080250 - PMCID: PMC7033139 - DOI: 10.1038/s41598-020-59658-0
Mpekris F, Voutouri C, Baish JW, Duda DG, Munn LL, Stylianopoulos T, Jain RK
Combining microenvironment normalization strategies to improve cancer immunotherapy.
Proc Natl Acad Sci U S A. 2020;117(7):3728-3737 - PMID: 32015113 - PMCID: PMC7035612 - DOI: 10.1073/pnas.1919764117
Munn LL, Jain RK
Vascular regulation of antitumor immunity.
Science. 2019;365(6453):544-545 - PMID: 31395771 - PMCID: PMC7321824 - DOI: 10.1126/science.aaw7875
Munn LL, Garkavtsev I
SLPI: a new target for stopping metastasis.
Aging (Albany NY). 2018;10(1):13-14 - PMID: 29356683 - PMCID: PMC5811255 - DOI: 10.18632/aging.101372
Bazou D, Maimon N, Gruionu G, Grahovac J, Seano G, Liu H, Evans CL, Munn LL
Vascular beds maintain pancreatic tumor explants for ex vivo drug screening.
J Tissue Eng Regen Med. 2018;12(1):e318-e322 - PMID: 28568605 - PMCID: PMC5711628 - DOI: 10.1002/term.2481
Munn LL
Cancer and inflammation.
Wiley Interdiscip Rev Syst Biol Med. 2017;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, 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
Padera TP, Meijer EF, Munn LL
The Lymphatic System in Disease Processes and Cancer Progression.
Annu Rev Biomed Eng. 2016;18:125-58 - PMID: 26863922 - PMCID: PMC4946986 - DOI: 10.1146/annurev-bioeng-112315-031200
Kunert C, Baish JW, Liao S, Padera TP, Munn LL
Mechanobiological oscillators control lymph flow.
Proc Natl Acad Sci U S A. 2015;112(35):10938-43 - PMID: 26283382 - PMCID: PMC4568261 - DOI: 10.1073/pnas.1508330112
Munn LL
Mechanobiology of lymphatic contractions.
Semin Cell Dev Biol. 2015;38:67-74 - PMID: 25636584 - DOI: 10.1016/j.semcdb.2015.01.010
Qazi H, Palomino R, Shi ZD, Munn LL, Tarbell JM
Cancer cell glycocalyx mediates mechanotransduction and flow-regulated invasion.
Integr Biol (Camb). 2013;5(11):1334-43 - PMID: 24077103 - PMCID: PMC4249644 - DOI: 10.1039/c3ib40057c
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. 2012;109(3):911-6 - PMID: 22203958 - PMCID: PMC3271885 - DOI: 10.1073/pnas.1118910109
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