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Mihaela Skobe

  • ASSOCIATE PROFESSOR Oncological Sciences
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Education

  • B.S., University of Zagreb
    Molecular Biology

  • Ph.D., University of Heidelberg
    Cell Biology

  • Harvard Medical School/Massachussetts General Hospital

Research

The main research interest of my laboratory is in understanding the mechanisms of cancer metastasis via the lymphatic system and the function of lymphatic vessels in the regulation of immune response.

Metastasis is the main cause of treatment failure and death for cancer patients. The first site to which cancer cells metastasize are lymph nodes, and the extent of lymph node involvement is a major criterion for evaluating patient prognosis and the choice of therapy. Despite the fact that the importance of the lymphatic system as a pathway for cancer metastasis has been well recognized, research efforts over the past decades have been focused primarily on understanding the mechanisms of tumor spread via the blood vasculature. Thus, the mechanisms of tumor spread via the lymphatic system remain poorly understood. Aside from serving as a transport system for tumor cells, the lymphatic system normally collects extravasated fluid, macromolecules and leukocytes from tissues and returns them to the blood circulation. By directing antigen-presenting cells, T-cells and antigens from peripheral tissues into the lymph nodes, lymphatic vessels play an important role in the initiation of immune response. However, the mechanisms by which leukocytes are mobilized into the lymphatic vessels are poorly understood, and in particular, the role of lymphatic vessels in the process remains unknown.

Our long-term research efforts are dedicated towards elucidating the molecular mechanisms which regulate lymphatic vessel growth (i.e. lymphangiogenesis) and the function of lymphatic vessels in cancer and in normal physiology. Current research includes investigations of the mechanisms by which tumor cells interact with the lymphatic vasculature during early steps of metastasis. We are investigating the role of role of chemokines and cell adhesion molecules expressed by the lymphatic endothelium in tumor invasion and metastasis, to gain insight into the mechanisms which regulate tumor cell migration and entry into the lymphatic vessels. We are also investigating the molecular mechanisms of lymphangiogenesis. Our previous studies have demonstrated that the induction of tumor lymphangiogenesis by the Vascular Endothelial Growth Factor-C (VEGF-C) facilitates tumor metastases. The goals of our current research activities are to better understand the mechanisms by which VEGF-C promotes metastasis and to assess the potential of VEGF-C and its receptors as targets for the anti-metastatic therapy. Our efforts are also dedicated towards identification of novel lymphangiogenic factors and markers of the lymphatic endothelium. Finally, the lab is exploring the role of lymphatic vasculature in the regulation of immune response, particularly its function in regulating migration and activation of antigen-presenting cells. The ultimate goal of these studies is to gain insight into the molecular mechanisms by which lymphatic endothelial cells control physiological cell migration and to examine whether tumor cells take advantage of these mechanisms to gain access to the lymphatic vessels. The knowledge gained with the above studies may provide a foundation for the development of new therapeutic approaches to predict, arrest and treat cancer metastases.

Graduate Students
Simona Podgrabinska, Bryan Kloos

Postdoctoral Fellows
Suvendu Das, Xiaodong Zhang

Clinical Research Fellow
Konstantin Zakashansky

Research Associate
Jeremy Medalle

Publications

Serasinghe MN, Missert DJ, Asciolla JJ, Podgrabinska S, Wieder SY, Izadmehr S, Belbin G, Skobe M, Chipuk JE. Anti-apoptotic BCL-2 proteins govern cellular outcome following B-RAF(V600E) inhibition and can be targeted to reduce resistance. Oncogene 2014 Mar; 0.

Podgrabinska S, Skobe M. Role of lymphatic vasculature in regional and distant metastases. Microvascular research 2014 Sep; 95C.

Das S, Sarrou E, Podgrabinska S, Cassella M, Mungamuri SK, Feirt N, Gordon R, Nagi CS, Wang Y, Entenberg D, Condeelis J, Skobe M. Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses. The Journal of experimental medicine 2013 Jul; 210(8).

Das S, Ladell DS, Podgrabinska S, Ponomarev V, Nagi C, Fallon JT, Skobe M. Vascular endothelial growth factor-C induces lymphangitic carcinomatosis, an extremely aggressive form of lung metastases. Cancer research 2010 Mar; 70(5).

Lederle W, Linde N, Heusel J, Bzyl J, Woenne EC, Zwick S, Skobe M, Kiessling F, Fusenig NE, Mueller MM. Platelet-derived growth factor-B normalizes micromorphology and vessel function in vascular endothelial growth factor-A-induced squamous cell carcinomas. The American journal of pathology 2010 Feb; 176(2).

Podgrabinska S, Kamalu O, Mayer L, Shimaoka M, Snoeck H, Randolph GJ, Skobe M. Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. Journal of immunology (Baltimore, Md. : 1950) 2009 Aug; 183(3).

Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, Borisenko V, Feirt N, Podgrabinska S, Shiraishi K, Chawengsaksophak K, Rossant J, Accili D, Skobe M, Kitajewski J. Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. The Journal of clinical investigation 2007 Nov; 117(11).

Furtado GC, Marinkovic T, Martin AP, Garin A, Hoch B, Hubner W, Chen BK, Genden E, Skobe M, Lira SA. Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proceedings of the National Academy of Sciences of the United States of America 2007 Mar; 104(12).

Lederle W, Stark HJ, Skobe M, Fusenig NE, Mueller MM. Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells. The American journal of pathology 2006 Nov; 169(5).

Grossmann C, Podgrabinska S, Skobe M, Ganem D. Activation of NF-kappaB by the latent vFLIP gene of Kaposi's sarcoma-associated herpesvirus is required for the spindle shape of virus-infected endothelial cells and contributes to their proinflammatory phenotype. Journal of virology 2006 Jul; 80(14).

Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, Pytowski B, Skobe M. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer research 2006 Mar; 66(5).

Angeli V, Ginhoux F, Llodrà J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 2006 Feb; 24(2).

Goldman J, Le TX, Skobe M, Swartz MA. Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin. Circulation research 2005 Jun; 96(11).

Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, Skobe M, Boardman KC, Swartz MA. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. Journal of the National Cancer Institute 2005 Jan; 97(1).

Sugaya M, Watanabe T, Yang A, Starost MF, Kobayashi H, Atkins AM, Borris DL, Hanan EA, Schimel D, Bryant MA, Roberts N, Skobe M, Staskus KA, Kaldis P, Blauvelt A. Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter. Blood 2005 Mar; 105(6).

Gruss CJ, Satyamoorthy K, Berking C, Lininger J, Nesbit M, Schaider H, Liu ZJ, Oka M, Hsu MY, Shirakawa T, Li G, Bogenrieder T, Carmeliet P, El-Deiry WS, Eck SL, Rao JS, Baker AH, Bennet JT, Crombleholme TM, Velazquez O, Karmacharya J, Margolis DJ, Wilson JM, Detmar M, Skobe M, Robbins PD, Buck C, Herlyn M. Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice. The Journal of investigative dermatology 2003 Apr; 120(4).

Podgrabinska S, Braun P, Velasco P, Kloos B, Pepper MS, Skobe M. Molecular characterization of lymphatic endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 2002 Dec; 99(25).

Szuba A, Skobe M, Karkkainen MJ, Shin WS, Beynet DP, Rockson NB, Dakhil N, Spilman S, Goris ML, Strauss HW, Quertermous T, Alitalo K, Rockson SG. Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 Dec; 16(14).

Hawighorst T, Skobe M, Streit M, Hong YK, Velasco P, Brown LF, Riccardi L, Lange-Asschenfeldt B, Detmar M. Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth. The American journal of pathology 2002 Apr; 160(4).

Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, Detmar M. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. The American journal of pathology 2001 Sep; 159(3).

Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature medicine 2001 Feb; 7(2).

Detmar M, Velasco P, Richard L, Claffey KP, Streit M, Riccardi L, Skobe M, Brown LF. Expression of vascular endothelial growth factor induces an invasive phenotype in human squamous cell carcinomas. The American journal of pathology 2000 Jan; 156(1).

Skobe M, Brown LF, Tognazzi K, Ganju RK, Dezube BJ, Alitalo K, Detmar M. Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and flt-4 are expressed in AIDS-associated Kaposi's sarcoma. The Journal of investigative dermatology 1999 Dec; 113(6).

Streit M, Velasco P, Brown LF, Skobe M, Richard L, Riccardi L, Lawler J, Detmar M. Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas. The American journal of pathology 1999 Aug; 155(2).

Bajou K, Noël A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nature medicine 1998 Aug; 4(8).

Skobe M, Fusenig NE. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proceedings of the National Academy of Sciences of the United States of America 1998 Feb; 95(3).

Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE. Halting angiogenesis suppresses carcinoma cell invasion. Nature medicine 1997 Nov; 3(11).

Industry Relationships

Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.

Dr. Skobe did not report having any of the following types of financial relationships with industry during 2013 and/or 2014: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.

Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.

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