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Prof. Melody Swartz - Role of lymphatic vessels in cancer invasion and metastasis

Prof. Melody Swartz

Associate Professor, Institute of Bioengineering and ISREC, EPFL

Melody Swartz received her BS in Chemical Engineering from Johns Hopkins University in 1991, and her PhD from MIT in 1998 under the direction of Rakesh Jain. She did a postdoc at Harvard in the group of Dr. Jeffrey Drazen of the Brigham & Women’s Hospital. In 1999, she moved to Northwestern University as an Assistant Professor of Biomedical Engineering, and after 3 years was recruited to the EPFL. Throughout her career, she has focused on the lymphatic system, integrating physiology, bioengineering, tissue mechanics, and cell biology to elucidate their functional-biological regulation and more recently how immune cells and cancer cells gain access to the lymphatics.
 
 

Ecole Polytechnique Fédérale (EPFL)

AAB 0 43 (Bâtiment AAB) Station 15
CH-1015 Lausanne
Switzerland
Tel: +41 21 693 96 83
Fax: +41 21 693 69 33
Email:
 

Lymphatics and the Tumor Microenvironment

The most common types of carcinomas disseminate through the lymphatic system, yet the mechanisms by which they gain access to the lymphatic system – and how they manipulate their microenvironment, including stromal cells and immune cells, to do so – are poorly understood. Our research is geared towards elucidating the functional biology of lymphatic endothelium and its active roles in immune cell trafficking and lymphatic metastasis of tumors. In particular, our interdisciplinary team examines how lymphatic function (i.e., to drain fluid and facilitate cell migration) can physically regulate its biology, particularly with respect to immune cell transport, and how tumors can hijack these mechanisms. We integrate in vivo, in vitro, and in silico approaches and have developed many novel model systems in which to study cancer-lymphatic interactions in vitro.

Interstitial and lymphatic flow in the tumor microenvironment

One example is in CCR7 signaling, which is used by immune cells to home to lymph nodes. Lymphatic endothelium secretes the CCR7 ligand CCL21, and dendritic cells chemotact up the CCL21 gradient to find lymphatics. Tumor metastasis to lymph nodes has been correlated with CCR7 expression, but highly invasive tumor cells also secrete CCR7 ligands, creating an apparent paradox since the autologous CCR7 ligands should render the tumor less sensitive to lymphatic-secreted chemokine. We are studying how tumor cells can use these to sense their biophysical environment - interstitial flow that drains into lymphatic vessels – as an “autologous chemotaxis” mechanism whereby self-secreted chemokines form local, extracellular gradients under flow, and tumor cells then ‘chemotact’ up this gradient to the nearest draining lymphatic vessel.
We also demonstrated that heightened interstitial flow, such as that induced by inflammation (and tumors), can drive fibroblast differentiation into myofibroblasts via autocrine TGF-b1. We are now studying how the lymphatic microenvironment – both physical (i.e., driving fluid flow) and chemical (i.e., lymphatic chemokines) – affects tumor-fibroblast-lymphatic interactions, all of which individually are highly sensitive to physical forces. We use novel in vitro systems that recapitulate key aspects of this microenvironment.

 

Role of lymphatics in tumor escape of immune surveillance

The lymphoid chemokine CCL21 not only attracts mature dendritic cells (DCs) to the lymphatic vessels and the lymph node, but also attracts naïve T cells so that DC-T cell interactions can effectively take place for T cell education. Our discovery that some invasive tumors also secrete CCL21 led us to study the role of tumor-secreted CCL21 on the host immune response to the tumor. We find that by secreting CCL21, tumors can attract high numbers of both antigen-presenting cells and naïve T cells such that T cell education can take place within the tumor’s highly tolerogenic cytokine environment, leading to a shift in the host immune response favoring tolerance over immunity.

Immunomodulatory functions of lymphatics

Upon tissue injury or inflammation, interstitial flow increases drastically and almost immediately. We are interested in how interstitial flow can act as an inflammatory cue to lymphatics and cause them to change their transport functions according to the cytokine environment, which indicates self vs. pathogenic signals and therefore helps to modulate the immune response towards tolerogenic or immunogenic. We also found that CCL21 expression in the lymph node is strongly regulated by flow and are examining the immunological implications of that.

Targeting lymphatics for immunomodulation

Other projects in our lab include targeting lymphatics and lymph nodes with immunomodulating nanoparticles in collaboration with Jeffrey Hubbell’s lab. We are currently using such approaches to develop lymph node-targeting cancer vaccines.

 

List of publications

Published papers with peer reviews
 

AA Tomei, S Siegert, MR Britschgi, SA Luther, and MA Swartz. Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node model. J Immunol (2009)

HY Lim, JM Rutkowski, J Helft, ST Reddy, MA Swartz, GJ Randolph, and V Angeli. Hypercholesterolemic mice exhibit lymphatic vessel dysfunction and degeneration. Am J Pathol (2009)

JB Dixon, S Raghunathan, MA Swartz. A tissue engineered model of the intestinal microenvironment for evaluating lipid uptake into lacteals. Biotech Bioeng 103(6):1224-35 (2009)

U Haessler, Y Kalinin, MA Swartz, and M Wu. An agarose-based microfluidic platform with a gradient buffer for 3D chemotaxis studies Biomed. Microdev. 11(4):827-835 (2009)

AA Tomei, F Boschetti, F. Gervaso, MA Swartz. Culturing 3D collagen cultures under well-defined dynamic strain: a novel strain device with a porous elastomeric support. Biotech Bioeng 103:217-225 (2009)

A Issa, TX Le, AN Shoushtari, JD Shields, MA Swartz. VEGF-C and CCL21 in tumor cell ­ lymphatic crosstalk promote invasive phenotype. Cancer Res. 69:349-357(2009)

M.A. Swartz, J.A. Hubbell, and S.T. Reddy. Lymphatic drainage function and its immunological implications: From dendritic cell homing to vaccine design. Semin. Immunol., 20(2):147-56 (2008)

A.A. Tomei, M.M. Choe, and M.A. Swartz. Effects of dynamic compression on Lentiviral transduction in an in vitro airway wall model. Am. J. Physiol. Lung Cell Mol. Physiol. 294:L79-L86 (2008)

S.T. Reddy, A.J. van der Vlies, E. Simeoni, V. Angeli, G.J. Randolph, M.A. Swartz, and J.A. Hubbell*. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nature Biotechnol. 25(10):1159-64 (2007)

J.D. Shields, M.E. Fleury, C. Yong, A.A. Tomei, G.J. Randolph, and M.A. Swartz. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11:526-538. (comment J. Cell Biol. 178:4; won Servier Award by the Microcirculatory Society in 2008) (2007)

M.E. Fleury and M.A. Swartz. Interstitial flow and its effects in soft tissues. Annu. Rev. Biomed. Eng. 9:229-56 (2007)

J. Goldman, J.M. Rutkowski, J.D. Shields, M.C. Pasquier, Y. Cui, H.G. Schmoekel, S. Wiley, D.J. Hicklin, B. Pytowksi, and M.A. Swartz. Cooperative and redundant roles of VEGFR-3 and VEGFR-2 signaling in adult lymphangiogenesis. FASEB J. 21(4):1003-12 (2007)

J Goldman, KA Conley, A Raehl, DM Bondy, B Pytowski, MA Swartz, JM Rutkowksi, DB Jaroch, and EL Ongstad. Regulation of lymphatic capillary regeneration by interstitial flow in skin. Am. J. Physiol, Heart Circ. Physiol. 292(5):H2176-83 (2007)

J.M. Rutkowski and M.A. Swartz. A driving force for change: Interstitial flow as a morphoregulator. Trends Cell Biol. 17(1):44-50 (2007)

C.E. Helm, A.H. Zisch, and M.A. Swartz. Engineered blood and lymphatic capillaries in 3D VEGF-fibrin-collagen matrices with interstitial flow. Biotech. Bioeng. 96(1):167-176 (2007)

JA Pedersen, F. Boschetti, and MA Swartz. Effects of extracellular matrix architecture on velocity and shear stress profiles on cells within a 3-D collagen matrix. J. Biomech. 40:1484-92 (2007)

ST Reddy, MA Swartz, and JA Hubbell*. Targeting dendritic cells with biomaterials: Developing the next generation of vaccines. Trends Immunol. 7(12):573-9 (2006)

ST Reddy, DA Berk , RK Jain , and MA Swartz. A sensitive in vivo model for quantifying interstitial transport of injected macromolecules and nanoparticles. J. Appl. Physiol. 101(4):1162-9 (2006)

MM Choe, AA Tomei, and MA Swartz (2006). 3D culture model of the human airway mucosa. Nature Protocols 1:357-362 (2006)

JM Rutkowski, M. Moya, J. Johannes, J. Goldman, and MA Swartz. Secondary lymphedema in the mouse tail: lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc. Res. 72:161-171 (2006)

JM Rutkowski, KC Boardman, and MA Swartz. Characterization of lymphangiogenesis in a model of adult skin regeneration. Am. J. Physiol. Heart Circ. Physiol. 291: H1402–H1410 (2006)

ME Fleury, KC Boardman, and MA Swartz. Autologous morphogen gradients by subtle interstitial flow and matrix interactions. Biophys. J. 91(1) 113–121 (2006)

MM Choe, PHS Sporn, and MA Swartz. Extracellular matrix remodeling by dynamic strain in a 3D airway wall model. Am. J. Resp. Cell Mol. Biol. 35(3):306-13 (2006)

LG Griffith and MA Swartz. Capturing complex 3D tissue physiology in vitro. Nature Rev. Mol. Cell Biol. 7:211-224 (2006)

ST Reddy, A. Rehor, HG Schmoekel, JA Hubbell, and MA Swartz. Targeting dendritic cells in lymph nodes with PPS-PEG nanoparticles. J. Contrl. Rel. 112(1):26-34 (2006)

CP Ng and MA Swartz. Mechanisms of interstitial flow-induced remodeling of fibroblast-collagen cultures. Ann. Biomed. Eng. 34(3):446-54 (2006)

LG Griffith, MA Swartz, and RT Tranquillo. Education for careers in tissue engineering and regenerative medicine. Ann. Biomed. Eng. 34(2):265-9 (2006)

CE Helm, ME Fleury, AH Zisch, F Boschetti, and MA Swartz. Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism. Proc. Natl. Acad. Sci. U.S.A. 44:15779-15784 (2005)

C Yong, EA Bridenberg, DC Zawieja, MA Swartz. Microarray analysis of VEGF-C responsive genes in cultured primary human lymphatic endothelial cells. Lymphatic Res. Biol. 3:183-207 (2005)

JA Pedersen and MA Swartz. Mechanobiology in the third dimension. Ann. Biomed. Eng. 33(11):1469-1490 (2005)

CP Ng, B Hinz, and MA Swartz. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J. Cell Sci. 118(20):4731-4739 (2005)

GJ Randolph, V Angeli, and MA Swartz. Dendritic cell trafficking to lymph nodes via lymphatic vessels. Nature Rev. Immunol. 5: 1-12 (2005)

J Goldman, TX Le, M Skobe, and MA Swartz. Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin. Circ. Res. 96:1193-1199 (Comment: Circ Res. 96:1132-1134, 2005) (2005)

B Pytowski, J Goldman, K Persaud, Y Wu, L Witte, DJ Hicklin, M Skobe, KC Boardman, and MA Swartz. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J. Natl. Cancer Inst. 97(1):14-21 (Comments: J. Natl. Cancer Inst. 97(1):1-2, 2005; Lab Invest. 85 (6): 719, 2005; Lymphatic Res. Biol. 3(2):87-88, 2005)(2005)

CP Ng, CE Helm, and MA Swartz. Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro. Microvasc. Res. 68(3):258-264 (2004)