Meenhard Herlyn, D.V.M., D.Sc.

Professor and Program Leader
Molecular and Cellular Oncogenesis Program
215-898-3950, Office
215-898-0980, Fax

Introduction

Research in the laboratory of Meenhard Herlyn centers on the basic mechanisms that govern normal cell function, or homeostasis. Knowing how cells and tissues orchestrate their intertwined purposes helps researchers establish what happens when things go awry, such as in cancerous tumors.

Research Interests

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

1. Modeling the normal and diseased human tissue microenvironment. Human embryonic stem cells and pluri-potent stem cells from the human dermis and epidermis 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 have developed a complex, three dimensional model mimicking the human skin.  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 microenvironment supports cells to survive the initial crisis. The synthetic skin model was expanded to organotypic cultures for oral cavity, esophagus, and breast. We can also introduce into each model endothelial cells forming a microcapillary network. Studies on interactions between tumor cells, fibroblasts and endothelial cells are done in three-dimensional models, in which cells are embedded into collagen to mimic the tumor microenvironment. Cells growth in tissue-like models induce major changes in gene expression similar to those in animals and patients making them superbly suited for studies on 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 in lentivirak vectors we are identifying those 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 additional pathways are explored to not only induce cytostatic but cytotoxic effects. Therapy is increasingly guided by the genetic aberrations in tumors and we are developing combinations of drugs 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 and therapy resistance. 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-propagating cells are central for 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 with a major focus on non-proliferating cells with high proliferation potential (label-retaining cells) hypothesizing that these are critical for dormancy and therapy resistance.  We are then defining the escape of tumor cells from dormancy for growth, invasion and metastasis and and developing strategies for therapy. Using our unique three-dimensional melanoma and squamous carcinoma models we are determining how microenvironmental cues drive gene activation that leads to a signaling cascade for proliferation and invasion.

LAB ROTATION PROJECTS FOR 2006-2007

1.  Development of a lentiviral vector to disrupt vessel morphogenesis by targeting Notch genes.
 
2.  Crosstalk 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 and epidermal stem cells
 
6.  Dedifferentiation of melanocytes to multi-potent stem cells

Selected Publications

1. 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
   
   
2. 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
   
   
3. Liu, Z.-J., Xiao, M., Balint, K., Smalley, K.S.M., Brafford, P., Qiu, E., Pinnix, C.C.,Li, X., Herlyn, M.: Notch1 signaling promotes primary melanoma progression by activating Mitogen-Activated Protein Kinase/Phosphatidylinositol 3-kKnase-Akt pathways and upregulating N-cadherin expression. Cancer Res 66: 4182-4190, 2006. PMID16618740
   
   
4. 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
   
   
5. Tsai, J., Lee, J.T., Wang, W. Zhang, J., Cho, H., Mamo, S., Bremer, R., Gilette, S., Kong, J., Haass, N.K., Sproesser, K., Li, L., Smalley, K.S.M., Fong, D., Zhu, Y-L., Marimuthu, A., Nguyen, H., Lam, B., Liu, J., Cheung, I., Rice, J., Suzuki, Y., Liu, C., Settachatgul, C., Shellooe, R., Cantwell, J., Kim, S-H, Schlessinger, J., Zhang, K.Y.J., West, B., Powell, B., Habets, G., Zhang, C., Ibrahim, P.N. Hirth, P., Artis, D.R., Herlyn, M., Bollag, G.: Discovery of a novel selective inhibitor of oncogenic B-Raf kinase with potent anti-melanoma activity. Proc. Nat. Acad. Sc. (USA) 26: 3041-3049, 2008. PMID18287029
   
   
6. Noma, K., Smalley, K.S.M., Lioni, M., Naomoto, Y., Tanaka, N., El-Deiry, W., King, A.J., Nakagawa, H., Herlyn, M.: An essential role for stromal fibroblasts and transformating growth factors (TGF)-ß in esophageal squamous cell carcinoma-induced angiogenesis. Gastroenterology March 4, [Epub ahead of print], 2008. PMID18439605
   
   
7. Smalley, K.S.M., Contractor, R., Nguyen, T.K., Xiao, M., Medinca, A., Edwards, R., Muthusamy, V., King, A.J., Flaherty, K.T., Bosenberg, M., Herlyn, M., Nathanson, K.L.: Identification of a novel sub-group of melanomas with c-kit/CDK4 co-amplification and sensitivity to imatinib mesulate (Gleevec®). Cancer Res., in press, 2008.
   
   
8. Zabierowski, S.E., and Herlyn, M.: Melanoma stem cells: the dark seed of melanoma. J Clin. Oncol.: 26:2890-2894, 2008, PMID 18539969
   
   
9. Pinnix, C.C., and Herlyn, M.: The many faces of Notch signaling in skin-derived cells. Pigment Cell Res. 20: 458-465, 2007. PMID 17935489