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Timothy Padera
Associate Prof., Radiation Oncology

Padera Lab Research

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.

Lab News

Metastatic lymph nodes can be the source of distant metastases in mouse models of cancer

If confirmed in human patients, findings could indicate the need to treat lymph node metastases

A study by Massachusetts General Hospital (MGH) investigators finds that, in mouse models, cancer cells from metastatic lymph nodes can escape into the circulation by invading nodal blood vessels, leading to the development of metastases in other parts of the body. Their report appearing in the March 23 issue of Science adds evidence to the debate regarding the role of lymph node metastases in the spread of cancer. 

Article in Science ...

Mass. General study reveals how MRSA infection compromises lymphatic function

Bacterial toxins kill lymphatic muscle cells, raising risk of recurrent infection

Development of new blood vessels not essential to growth of lymph node metastases
Dr. Padera's research group recently published in Journal of the National Cancer Institute that the growth of metastases in lymph nodes does not require new blood vessels but instead takes advantage of existing blood vessels. This may, in part, explain why antiangiogenesis therapies have been largely ineffective in preventing new metastases. See the press release here.

Padera Lab Careers

Postdoctoral Fellow

Investigator: Padera, Timothy
Date Posted: 2018-04-11
Description
Postdoctoral Research position at Harvard Medical School and the Edwin L. Steele Laboratories at Massachusetts General Hospital. The Padera Laboratory is currently seeking postdoctoral applicants with training and research experience in tumor biology to carry out exciting multidisciplinary projects aimed at understanding the role of lymph node metastasis in the progression of cancer and the suppression of anti-tumor immunity. A strong background in molecular biology and biochemistry as well as experience with animal models is preferred. Candidates with experience with bioinformatic approaches are encouraged to apply.
Requirements
Individuals 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. Applicants with a strong training background and publication track record in tumor biology and immunology are encouraged to apply. Experience in the following technical areas is preferred: molecular biology, biochemistry, imaging and murine models of cancer. US citizens and permanent US residents are encouraged to apply. To begin the application process, please e-mail a current CV and statement of purpose to tpadera@steele.mgh.harvard.edu.

Postdoctoral Fellow

Investigator: Padera, Timothy
Date Posted: 2018-04-11
Description
Postdoctoral Research position at Harvard Medical School and the Edwin L. Steele Laboratories at Massachusetts General Hospital. The Padera Laboratory is currently seeking postdoctoral applicants with training and research experience in vascular biology or bioengineering to carry out exciting multidisciplinary projects aimed at understanding the role of the lymphatic system plays in a variety of disease processes, including recurrent bacterial infections, lymphedema and immune suppression associated with aging. A strong background in imaging, image processing and animal modeling is preferred.
Requirements
Individuals 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. Applicants with a strong training background and publication track record in lymphatic/vascular biology, immunology or infectious disease are encouraged to apply. Experience in the following technical areas is preferred: biochemistry, imaging, bioengineering and murine models. US citizens and permanent US residents are encouraged to apply. To begin the application process, please e-mail a current CV and statement of purpose to tpadera@steele.mgh.harvard.edu.

Selected Publications (from total of 65)

Pereira ER, Kedrin D, Seano G, Gautier O, Meijer EFJ, Jones D, Chin SM, Kitahara S, Bouta EM, Chang J, Beech E, Jeong HS, Carroll MC, Taghian AG, Padera TP
Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice.
Science. 2018;359(6382):1403-1407 - PMID: 29567713 - PMCID: PMC6002772 - DOI: 10.1126/science.aal3622
Jones D, Meijer EFJ, Blatter C, Liao S, Pereira ER, Bouta EM, Jung K, Chin SM, Huang P, Munn LL, Vakoc BJ, Otto M, Padera TP
Methicillin-resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction.
Sci Transl Med. 2018;10(424):ePub - PMID: 29343625 - PMCID: PMC5953194 - DOI: 10.1126/scitranslmed.aam7964
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 - DOI: 10.1038/nprot.2017.045
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 - DOI: 10.1038/srep29035
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
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 - DOI: 10.1093/jnci/djv155
Chauhan VP, Boucher Y, Ferrone CR, Roberge S, Martin JD, Stylianopoulos T, Bardeesy N, DePinho RA, Padera TP, Munn LL, Jain RK
Compression of Pancreatic Tumor Blood Vessels by Hyaluronan Is Caused by Solid Stress and Not Interstitial Fluid Pressure.
Cancer Cell. 2014;26(1):14-15 - PMID: 25026209 - PMCID: PMC4381566 - DOI: 10.1016/j.ccr.2014.06.003
Liao S, Cheng G, Conner DA, Huang Y, Kucherlapati RS, Munn LL, Ruddle NH, Jain RK, Fukumura D, Padera TP
Impaired lymphatic contraction associated with immunosuppression.
Proc Natl Acad Sci U S A. 2011;108(46):18784-9 - PMID: 22065738 - PMCID: PMC3219138 - DOI: 10.1073/pnas.1116152108
Vakoc BJ, Lanning RM, Tyrrell JA, Padera TP, Bartlett LA, Stylianopoulos T, Munn LL, Tearney GJ, Fukumura D, Jain RK, Bouma BE
Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging.
Nat Med. 2009;15(10):1219-23 - PMID: 19749772 - PMCID: PMC2759417 - DOI: 10.1038/nm.1971
Plotkin SR, Stemmer-Rachamimov AO, Barker FG, Halpin C, Padera TP, Tyrrell A, Sorensen AG, Jain RK, di Tomaso E
Hearing improvement after bevacizumab in patients with neurofibromatosis type 2.
N Engl J Med. 2009;361(4):358-67 - PMID: 19587327 - PMCID: PMC4816642 - DOI: 10.1056/NEJMoa0902579
Hagendoorn J, Padera TP, Yock TI, Nielsen GP, di Tomaso E, Duda DG, Delaney TF, Gaissert HA, Pearce J, Rosenberg AE, Jain RK, Ebb DH
Platelet-derived growth factor receptor-beta in Gorham's disease.
Nat Clin Pract Oncol. 2006;3(12):693-7 - PMID: 17139320 - PMCID: PMC2693369 - DOI: 10.1038/ncponc0660
Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK
Pathology: cancer cells compress intratumour vessels.
Nature. 2004;427(6976):695 - PMID: 14973470 - DOI: 10.1038/427695a
Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK
Lymphatic metastasis in the absence of functional intratumor lymphatics.
Science. 2002;296(5574):1883-6 - PMID: 11976409 - DOI: 10.1126/science.1071420
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