Padera, Timothy, PhD

Padera
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Pathophysiology of tumor associated lymphatic vessels and lymphatic metastasis

Lymphatic vessels are responsible for draining interstitial fluid from tissues and for transporting immune cells to lymph nodes to maintain the body’s immune surveillance. Thus, lymphatics are important in maintaining both tissue fluid balance and proper function of the immune system. Predictably, disruptions of the lymphatic system lead to lymphedema and the conditions for chronic infections. Lymphatic vessels also facilitate the dissemination of cancer cells from a primary tumor to regional lymph nodes. My research group looks to understand the mechanisms behind the growth, maturation and function of lymphatic vessels and how these mechanisms can contribute to the pathogenesis of lymphedema, chronic infections and cancer dissemination.

In order to study the role of the lymphatic system in a variety of disease states, we have developed novel animal models which mimic certain aspects of human disease. Using intravital microscopy, we have investigated the individual steps of lymphatic metastasis. We can monitor the lymphatic vessels in the tumor margin, observe tumor cells moving in lymphatic vessels, measure lymph flow and quantify the number of tumor cells that arrive in the draining lymph node. Our studies have shown that VEGF-C, which is associated with lymphatic metastasis in patients, increases the size of the tumor margin lymphatic vessels, making them more vulnerable to invasion. Our data suggests that VEGF-C needs to be blocked very early in the metastatic process to be able to reduce VEGF-C enhanced lymphatic metastasis. Furthermore, we have shown that VEGFR targeted agents are not effective in preventing the growth of cancer cells that have seeded the lymph node, questioning the ability of these therapies to be used in the adjuvant setting.

To further study the growth of metastasis in the lymph node, we have developed a novel model that allows chronic imaging of a tumor draining lymph node. Using our model, we will ask fundamental questions underlying the growth of cancer cells in the lymph node and begin to identify molecular targets for future therapies aimed at eradicating lymphatic metastasis.
In addition, we have begun to study the pathogenesis of lymphedema by unraveling the molecular underpinnings of autonomous contraction of collecting lymphatic vessels using a novel animal model. We have shown that the spatial and temporal gradients of nitric oxide, which are disrupted during inflammation, are critical for lymphatics to drive lymph forward. Furthermore, when lymphatic contractions are disrupted, the immune response to a foreign antigen is muted. Thus disruption of lymphatic function has consequences for the overall immune function. We will test whether cancer or bacterial infections invoke similar regulatory dysfunction of lymphatic contraction. This work may lead to new targets to combat lymphedema and infections.

Our future studies will continue to dissect the physical and molecular determinants of lymphatic vessel function, lymphangiogenesis and lymphatic metastasis. Through the use of our novel imaging technologies and animal models, we will answer timely questions that can lead to the development of treatments for lymphedema, chronic infections and lymphatic metastasis.

Selected Publications (from total of 61)

Jung K, Heishi T, Incio J, Huang Y, Beech EY, Pinter M, Ho WW, Kawaguchi K, Rahbari NN, Chung E, Kim JK, Clark JW, Willett CG, Yun SH, Luster AD, Padera TP, Jain RK, Fukumura D
Targeting CXCR4-dependent immunosuppressive Ly6C(low) monocytes improves antiangiogenic therapy in colorectal cancer.
Proc Natl Acad Sci U S A. 2017;114(39):10455-10460 - PMID: 28900008 - PMCID: PMC5625928
Lippok N, Villiger M, Albanese A, Meijer EFJ, Chung K, Padera TP, Bhatia SN, Bouma BE
Depolarization signatures map gold nanorods within biological tissue.
Nat Photonics. 2017;11:583-588 - PMID: 29201136 - PMCID: PMC5703429
Blatter C, Meijer EFJ, Padera TP, Vakoc BJ
Simultaneous measurements of lymphatic vessel contraction, flow and valve dynamics in multiple lymphangions using optical coherence tomography.
J Biophotonics. 2017;:ePub - PMID: 28700145
Jung K, Heishi T, Khan OF, Kowalski PS, Incio J, Rahbari NN, Chung E, Clark JW, Willett CG, Luster AD, Yun SH, Langer R, Anderson DG, Padera TP, Jain RK, Fukumura D
Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy.
J Clin Invest. 2017;127(8):3039-3051 - PMID: 28691930 - PMCID: PMC5531423
Meijer EFJ, Jeong HS, Pereira ER, Ruggieri TA, Blatter C, Vakoc BJ, Padera TP
Murine chronic lymph node window for longitudinal intravital lymph node imaging.
Nat Protoc. 2017;12(8):1513-1520 - PMID: 28683064 - PMCID: PMC5592697
Meijer EF, Blatter C, Chen IX, Bouta E, Jones D, Pereira ER, Jung K, Vakoc BJ, Baish JW, Padera TP
Lymph node effective vascular permeability and chemotherapy uptake.
Microcirculation. 2017;:ePub - PMID: 28510992 - PMCID: PMC5706450
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
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
Meijer EF, Baish JW, Padera TP, Fukumura D
Measuring Vascular Permeability In Vivo.
Methods Mol Biol. 2016;1458:71-85 - PMID: 27581015 - PMCID: PMC5435480
Blatter C, Meijer EF, Nam AS, Jones D, Bouma BE, Padera TP, Vakoc BJ
In vivo label-free measurement of lymph flow velocity and volumetric flow rates using Doppler optical coherence tomography.
Sci Rep. 2016;6:29035 - PMID: 27377852 - PMCID: PMC4932526
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
Kunert C, Baish JW, Liao S, Padera TP, Munn LL
Reply to Davis: Nitric oxide regulates lymphatic contractions.
Proc Natl Acad Sci U S A. 2015;113(2):E106 - PMID: 26719425 - PMCID: PMC4720299
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
Jeong HS, Jones D, Liao S, Wattson DA, Cui CH, Duda DG, Willett CG, Jain RK, Padera TP
Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases.
J Natl Cancer Inst. 2015;107(9):ePub - PMID: 26063793 - PMCID: PMC4651102
Kesler CT, Pereira ER, Cui CH, Nelson GM, Masuck DJ, Baish JW, Padera TP
Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation.
FASEB J. 2015;29(9):3668-77 - PMID: 25977256 - PMCID: PMC4550378
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