Meenhard Herlyn, D.V.M., D. Sc.
Professor, Dept of Molecular and Cellular Oncogenesis

Cancer Biology Program

Address

487 Wistar Institute (Office)
489 Wistar Instituate (Lab)
3601 Spruce St
Philadelphia, PA 19104

Office tel.: 215 898-3950
Lab tel.: 215 898-3951
Fax: 215 898-0980
E-mail: herlynm@wistar.org

Link(s)

Dr. Herlyn's Wistar Website Dr. Herlyn's Lab page

EDUCATION

Veterinary School, Hannover, Germany: D.V.M., 1970.

University of Munich, Germany: Sc.D. (Medical Microbiology), 1976.

RESEARCH INTERESTS

• Stem cells in tumor development, progression and therapy

Key words: Tumor development, progression, metastasis, stem cells, skin, esophagus, breast, and vessel morphogenesis.

Search PubMed for articles

DESCRIPTION OF RESEARCH

Cells in normal tissues maintain a life-long homeostatic balance, in which growth, differentiation, and cell death are dynamically regulated. To establish and maintain normal organ structure and function, cells must remain within their predestined locations. The delicate balance among organ-specific cells within the scaffolding of matrix proteins is disturbed during tumor development. Transformed cells escape from homeostasis and destroy normal tissue architecture. Our laboratory is interested in defining normal tissue homeostasis including the role of stem cells in organ maintenance and understanding pathological changes during cancer development and progression. This knowledge is increasingly used to develop new strategies for therapy.

1. Biology of Normal and Malignant Stem Cells (Mingyuan Zhou, Ph.D., Susan Zabierowski, Ph.D., Patricia Brafford, M.S., Ling Li, M.D., Katrin Sproesser, M.S., Jennifer Marmion, B.S., Ben Himes). Human embryonic stem cells and pluri-potent stem cells from the human dermis are differentiated into melanocytes to test the hypothesis that melanocyte stem cells are more prone to transformation than fully differentiated cells and that neighboring cells and matrix in the microenvironment play critical roles in differentiation and transformation. We are then characterizing melanoma stem cells (tumor-initiating cells) from melanoma spheres that represent a subpopulation in malignant lesions and that have characteristics of stem cells. We are distinguishing four populations of melanoma cells with stem cell-like characteristics: a. CD20+ cells, b. side population cells with increased drug resistance, c. label-retaining cells that turn over very slowly, and d. CD133 positive cells. Investigations of cancer stem cells will help us to understand tumor dormancy, recurrence, metastasis, and therapy resistance. Our primary model is melanocyte/melanoma but the laboratory is also investigating the role of tumor stem cells in carcinomas of esophagus, kidney, oral cavity, lung and breast.
2. Transformation (John Lee, Ph.D., Jessie Villanueva, Ph.D., Ronan McDaid, B.S., Jun Kong, M.S., Himatibindu Gaddipati, M.D., Gao Zhang, Patricia Possik, M.S.) The development of melanoma is a complex process, in which environmental cues such as ultraviolet light and activation of signaling pathways lead to uncontrolled proliferation. We are testing the hypothesis that melanocyte stem cells are the primary target for transformation to melanoma. Using a complex model of skin equivalents mimicking the human skin microenvironment the laboratory is reconstructing each step in the melanoma progression cascade. Genes associated with melanoma are overexpressed or expression is silenced with shRNAi constructs in lentiviral vectors. Our recent experiments suggest that as few as two genetic 'hits' can induce malignant transformation of melanocytes if the microenvironmental conditions are supporting cells to survive the initial crisis.
3. Targeted Therapies (Keiran Smalley, Ph.D., Mercedes Lioni, M.D., Bin Li, Ph.D., Kazuhiro Noma, M.D., Rooha Contractor, M.S., Brijal Desai, M.S., Min Xiao, M.S., Thiennga Nguyen, M.S.). We are defining the signal transduction pathways that are constitutively activated in melanoma cells through autocrine and paracrine growth factors and through genetic alterations. Through RNAi approaches we are selecting those genes in tumor cells and stromal fibroblasts that are potential targets for therapy. Three-dimensional culture models and orthotopic in vivo models are proving ideal for selecting small molecules as therapeutics in melanoma and esophageal and renal carcinomas. In melanoma, the MAPK pathway is the primary target for therapy but additional pathways need to be explored to not only induce cytostatic but cytotoxic effects. We expect that melanoma stem cells require strategies for elimination that are different from those targeting the main population. In esophagus carcinoma, therapy is even more difficult as these cells show astounding resistance to all conventional therapies. In both esophageal and renal cell cancer, tumor vascularization and its targeting is a major subject for our investigations.
4. Tumor Dormancy (Mizuho Fukunaga M.D., Ph.D., Gabriela Martinez, M.S., Ademi Santiago-Walker, Ph.D., Devraj Basu, M.D., Ph.D., Alexander Roesch, M.D., Sarah Telson). Dormancy of tumor cells can occur in primary lesions or at any time after metastatic dissemination and can last for many years. Our working hypothesis is that tumor stem cells (tumor-initiating cells or tumor cells with self-renewing capacity) are central for dormancy due to their non-proliferation or very slow turnover and their non-responsiveness to growth signals. We are defining tumor dormancy in melanoma and characterize stem cell populations with a major focus on non-proliferating cells with high proliferation potential (label-retaining cells) hypothesizing that these are critical for maintaining dormancy. We are then defining the escape of tumor stem cells from dormancy for growth, invasion and metastasis and develop strategies for therapy. The hypothesis is that activation of Notch signaling is key for melanoma stem cells to break out of dormancy. Notch signaling activates both MAPK and PI3K signaling pathways and leads to a highly invasive and metastatic phenotype. Using our unique three-dimensional melanoma models we are determining how microenvironmental cues drive Notch activation that leads to a signaling cascade for proliferation and invasion.
5. Stem cells in Breast Tumor Development and Therapy (Jung-im Huh, Ph.D., Julia Tchou, M.D., Ph.D, Adina Vultur, Ph.D. [expected Oct.07]. This evolving program seeks to define stem cells for both normal and malignant breast tissues and develop novel models for premalignant and malignant breast diseases that will provide the future basis for rational therapies.

RECENT PUBLICATIONS

Fukunaga-Kalabis, M., Martinez, G., Liu, Z.-J., Kalabis, J., Mrass, P., Weninger, W., Firth, S.M., Planque, N., Perbal, B., Herlyn, M. CCN3 controls 3D spatial localization of melanocytes in the human skin through DDR1. J Cell Biol. 175: 563-569, 2006. PMID 17101694

Yu, H., Fang, D., Kumar, S.M., Li, L., Nguyen, T. K., Acs, G., Herlyn, M., Xu, X.: Isolation of a novel population of multipotent adult stem cells from human hair follicles. Am J Pathol 168:1879-1988, 2006. PMID16723703

Fang, D., Leishear, K., Nguyen, T.K., Finko, R., Cai, K., Fukunaga, M., Li, L., Brafford, P.A., Kulp, A.N., Xu, X., Smalley, K.S., Herlyn, M.: Defining the conditions for the generation of melanocytes from human embryonic stem cells. Stem Cells 24:1668-1677, 2006. PMID 16574754

8. Lioni, M., Brafford, P., Andl, A., Rustgi, A., El-Deiry, W., Herlyn, M., Smalley, K.S.M.: Dysregulation of Claudin-7 leads to loss of E-cadherin expression and the increased invasion of esophageal squamous cell carcinoma cells. Am. J. Pathol. 170: 709-721, 2007. PMID 17255337

9. Smalley, K.S.M., Contractor, R., Haass, N.K., Kulp, A. N., Atilla-Gokcumen, G.E., Williams, D.S., Bregman, H., Flaherty, K.T., Soengas, M.S., Meggers, E., Herlyn, M.: A organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells. Cancer Res. 67: 209-217, 2007. PMID 17210701

Lab

ROTATION PROJECTS

1. Development of a lentiviral vector to disrupt vessel morphogenesis by targeting Notch genes.
2. Cross talk between the MAPK and AKT pathways in normal human melanocytes using adenoviral vectors.
3. Targeting BRAF and AKT in tissue-like models of melanoma with signaling antagonists and RNAi.
4. Human embryonic stem cell differentiation to melanocytes.
5. Matrix differentiation of dermal stem cells.

Lab personnel:

Senior Scientists
Keiran Smalley, Ph.D.
Mingyuan Zhou, Ph.D.

Staff Scientists
Mizuho Fukunaga-Kalabis, M.D., Ph.D.
Jung-im Huh, Ph.D.
Postdoctoral Fellows
John Lee, Ph.D.
Mercedes Lioni, M.D.,
Susan Zabierowski, Ph.D.
Jessie Villeueva, Ph.D.
Ademi Santiago-Walker, Ph.D.
Idena Vultur, Ph.D.

Visiting Scientists
Kazuhiro Noma,, M.D.
Julia Tchou, M.D., Ph.D.
Alexander Roesch, M.D.
Patricia Possik, M.S.
Himabindu Gaddipati, M.D.
Bin Li, Ph.D.
Brijal Desai, M.D.
Dev Basu, Ph.D.

Research Technicians
Patricia Brafford, MS
Ling Li, M.D.
Nga Nguyen, B.S.
Ronan McDaid, B.S.
Jennifer Marmion, B.S.
Rooha Contractor, M.S.
Jun Kong, M.S.
Katrin Sproesser, M.S.
Gabriela Martinez
Min Xiao, M.S.
Undergraduate Students
Sarah Telson
Ben Himes

Grants Administrator
Jessica Blodgett, M.B.A.

Office Manager
Sandy Parsons