Meenhard Herlyn, DVM,DSc

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Wistar Institute Professor of Dermatology
Department: Dermatology
Graduate Group Affiliations

Contact information
The Wistar Institute, Rm 472
3601 Spruce St.
Philadelphia, PA 19104
Office: 215-898-3950
Fax: 215 898-0980
Veterinary School, Hannover, Germany, 1970.
Sc.D. (Medical Microbiology)
University of Munich, Germany, 1976.
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Description of Research Expertise

Research Interests
Studying the normal and malignant tissue environment to develop rational approaches to cancer therapy

Key words: Stem cells in tissue morphogenesis, signal transduction and tumor development and progression, targeted therapy

Description of Research
1. Modeling the normal and diseased human tissue microenvironment. We are differentiating pluri-potent stem cells from the human dermis reprogrammed stem cells 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 have developed a complex, three-dimensional model that mimics human skin, and are using it to reconstruct each step in the melanoma development and progression cascade. Genes associated with melanoma are overexpressed or silenced with shRNA constructs in lentiviral vectors and we increasingly use cDNA and shRNA libraries for our experiments. The synthetic skin model has also been expanded to organotypic cultures for the esophagus. We can introduce into each model endothelial cells to form a microcapillary network and peripheral blood mononuclear cells to mimic the innate and immune host response. Studies on interactions among tumor cells, fibroblasts and endothelial cells are also done in three-dimensional models, in which cells are embedded into collagen to mimic the tumor microenvironment. Growing cells in these tissue-like models induces major changes in gene expression similar to those in animals and patients, making them superbly suited for studies of cell-cell signaling, matrix formation, and drug resistance.

2. Therapeutic targeting of signaling pathways in cancer. We are defining the signal transduction pathways that are constitutively activated in melanoma and squamous cell cancer cells through autocrine and paracrine growth factors and genetic alterations. With short-hairpin RNA (shRNA) in lentiviral vectors, we are identifying genes in tumor cells, stromal fibroblasts, and endothelial cells that are potential targets for therapy. In melanoma, the MAPK and PI3K pathways are primary targets for therapy, but other pathways are also explored for inhibition by small molecule compounds. Since therapy is increasingly guided by the genetic aberrations in tumors, we are developing combinations of compounds that take into account the genetic signature of tumors, with the long-term goal of individualized cancer therapy. Up to now, we have collaborated with pharmaceutical companies to obtain compounds in early stages of preclinical and clinical development. Increasingly, we are collaborating with academic chemists and structural biologists to select and further develop compounds for tumor inhibition.

3. Tumor dormancy, heterogeneity, and therapy resistance. Tumor cells can become dormant in primary tumors or at any time after metastatic dissemination and can persist in the dormant state for many years, allowing them to resist treatment. Our working hypothesis is that tumor-maintenance cells (tumor stem cells) are central to dormancy due to their non-proliferation or very slow turnover and their non-responsiveness to growth signals. We are delineating tumor dormancy in melanoma and characterizing sub-populations of cells with a major focus on non-proliferating cells that have high proliferation potential (label-retaining cells), hypothesizing that these cells are critical for dormancy and therapy resistance. We are then defining how tumor cells escape dormancy for growth, invasion, and metastasis, and developing strategies for therapy. Using our unique three-dimensional melanoma and squamous cell carcinoma models, we are determining how microenvironmental cues drive gene activation, leading to a signaling cascade for proliferation and invasion. These studies will lead to in-depth investigations of tumor heterogeneity and the dynamic regulation of genes that define sub-populations with specialized biologic functions. Our long-term goal is to develop strategies for two therapies, one for eliminating the bulk of the tumor, the other for small sub-populations that escape all major therapeutic approaches. Such combinations should achieve elimination of all tumor cells, which is required in melanoma because single tumor cells are capable of tumor induction in immunodeficient animals.

Rotation Projects:
1. Development of a lentiviral vector to disrupt melanocyte stem cell differentiation by targeting Notch genes.
2. Crosstalk between the MAPK and AKT pathways in normal human melanocytes.
3. Screen for compounds to activate p53
4. Target slow cycling tumor cells
4. Human stem cell differentiation to melanocytes
5. Induce pluri-potent stem cells from fibroblasts
6. Dedifferentiate melanocytes to multi-potent stem cells
7. Define drug-induced senescence in melanoma

Selected Publications

108. Herlyn, M., Villanueva, J: Sorting through the many opportunities for melanoma research. Pigm Cell Melanoma Res 24: 975-977, Oct 2011.

Li, L., Fukunaga-Kalabis, M., Herlyn, M: The three-dimensional human skin reconstruct model: a tool to study normal skin and melanoma progression329. J. Vis. Exp. 2011 Notes:

327. Basu, D., Montone, K.T., Wang, L-P, Gimotty, P.A., Hammond, R., Diehl, J.A., Rustgi, A.K., Lee, J.T., Rasanen, K, Weinstein, G.S., Herlyn, M: Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas. Cell Cycle 10: 2008-2016, 2011.

331. Zabierowski, S.E., Baubet, V., Himes, B, Li, L., Fukunaga-Kalabis, M., Patel, S., McDaid, R., Guerra, M., Gimotty, P., Dahamne, N., and Herlyn, M: Direct reprogramming of melanocytes to neural crest stem-like cells by one defined factor. Stem Cells 11: 1752-1762, 2011.

105. Fukunaga-Kalabis, M., Roesch, A., Herlyn, M: From cancer stem cells to tumor maintainenance cells. J Invest Dermatol 131: 1600-1604, 2011.

106. Villanueva, J., Vultur, A., Herlyn, M: Resistance to BRAF inhibitors: Unraveling mechanisms and future treatment options. Cancer Res 2011 Notes: IN PRESS.

103. Zabierowski, S.E., Fukunaga-Kalabis, M., Li, L., Herlyn, M: Dermis-derived stem cells: A source of epidermal melanocytes and melanoma? Pigm Cell Melanoma Res 24: 422-429, 2011.

104. Vultur, A., Villanueva, J., Herlyn, M.: Targeting BRAF in advanced melanoma: A first step towards manageable disease. Clin Can Res 17: 1658-1663, 2011.

Li, L., Fulunaga-Kalabis, M., Yu, H., Xu, X., Kong, J., Lee, J.T. Herlyn, M: Human dermal stem cells differentiate into functional epidermal melanocytes. J Cell Sci 123: 853-860, 2010.

Basu, D., Nguyen, T-T., Montone, K.T., Zhang, G., Wang, L-P., Diehl, J.A., Rustgi, A. K. Lee, J.T., Weinstein, G.S., Herlyn, M: Mesenchymal sub-populations within squamous cell carcinomas exhibiting chemoresistance and phenotypic plasticity. Oncogene 29: 4170-4182, 2010.

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Last updated: 11/22/2011
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