Prof. Meenhard Herlyn (PhD)

Professor in Melanoma Research

Director of the Melanoma Research Center at Wistar

 

 

wistar

ABOUT

Dr. Herlyn received his degree in Veterinary Medicine in 1970 at the Tier‰rztliche Hochschule in Hannover, Germany and his DSc degree in Medical Microbiology at the University of Munich, Germany.

In 1976 Dr. Herlyn joined the Wistar Institute in Philadelphia, PA. In 1991 he was appointed to the rank of Professor while also holding adjunct appointments in the Departments of Pathology and Dermatology at the University of Pennsylvania. In 2010 he became the Director of the newly established Melanoma Research Center. For the last 25 years he has continuously directed large, multi-disciplinary research programs on the etiology and therapy of melanoma.

Recent awards were from the American Skin Association, Melanoma Research Foundation, and the Society of Melanoma Research

  • Modeling the skin 89%
  • Therapy resistance 60%
  • Therapeutic targeting of signaling pathways 55%
  • Therapy resistance 35%

RESEARCH INTERESTS

Modeling the skin
We have developed complex, three-dimensional models that mimic human skin and are using it to reconstruct each step in the melanoma development and progression cascade. Normal melanocytes, keratinocytes, endothelial cells, inflammatory and immune cells, neural crest-like multi-potent stem cells from the dermis, and iPS cells are used to understand how cells communicate with each other and support or inhibit each other during the transformation process.

Therapeutic targeting of signaling pathways
We have defined signal transduction pathways that are constitutively activated in melanoma through autocrine and paracrine growth factors and genetic alterations.

Therapy resistance
To date, all strategies to therapeutically inhibit signaling induce intrinsic resistance of at least some tumor cells, which then re-populate the tumor and develop acquired resistance. Our objectives have been to understand the mechanisms of both types of resistance and how to overcome it.

Stem cells and melanoma
Melanoma cells are plastic and can readily adapt to a ëhostileí environment, such as tissue culture or growth in immunodeficient animals. Multi-potent or pluripotent stem cells that can give rise to melanocytes have similar properties. Thus stem cells can function as surrogates for melanoma cells and also for investigations on the cell of origin for this disease. Our work is focusing on iPS cells for generating skin and immune cells to investigate human tumor-(humanized) host interactions.

RELEVANT PUBLICATIONS (of >500 total)

  1. Modeling skin Meier F, Nesbit M, Hsu M-Y, Martin B, Van Belle P, Elder DE, Schaumburg-Lever G, Garbe C, Walz TM, Donatien P, Crombleholme TM, Herlyn M. Human melanoma progression in skin reconstructs : biological significance of bFGF. Am J Pathol. 2000;156:193-200. PMID10623667 (PMC1868639)
  2. Fukunaga-Kalabis M, Martinez G, Liu Z-J, Kalabis J, Mrass P, Weninger W, Firth SM, Planque N, Perbal B, Herlyn M. CCN3 controls 3D spatial localization of melanocytes in the human skin through DDR1. J Cell Biol. 2006;175:563-569. PMID17101694 (PMC2064593)
  3. Li L, Fukunaga-Kalabis M, Yu H, Xu X, Kong J, Lee JT, Herlyn M. Human dermal stem cells differentiate into functional epidermal melanocytes. J Cell Sci. 2010;123:853-860. PMID20159965 (PMC2831759)
  4. Fukunaga-Kalabis M, Hristova DM, Wang JX, Li L, Heppt MV, Wei Z, Gyurdiev A, Webster MR, Oka M, Weeraratna AT, Herlyn M. UV-induced Wnt7a in the human skin microenvironment specifies the fate of neural crest-like cells via suppression of Notch. J Invest Dermatol. 23 Feb 2015 [Epub ahead of print]. PMID25705850
  5. The biologic signature of melanoma
  6. Liu Z-J, Xiao M, Balint K, Smalley KSM, Brafford P, Qiu E, Pinnix CC, 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. 2006;66:4182-4190. PMID16618740
  7. Pinnix CC, Lee JT, Liu Z-J, McDaid R, Balint K, Beverly LJ, Brafford PA, Xiao M, Himes B, Zabierowski SE, Yashiro-Ohtani Y, Nathanson KL, Bengston A, Pollock PM, Weeraratna AT, Nickoloff BJ, Pear WE, Capobianco AJ, Herlyn M. Active Notch1 protein confers a transformed phenotype to primary human melanocytes. Cancer Res. 2009;69:5312-5320. PMID19549918 (PMC2755513)
  8. Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, Basu D, Gimotty P, Vogt T, Herlyn M. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010;141:583-594. PMID204782552 (PMC2882693).
  9. Fukunaga-Kalabis M, Martinez G, Nguyen T-TK, Kim D, Santiago-Walker A, Roesch A, Herlyn M. Tenascin promotes melanoma progression by maintaining the ABCB5-positive side population. Oncogene. 2010;29:6115-6124. PMID2072997 (PMC2991494)
  10. Therapeutic targeting Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gilette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KSM, 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 KYJ, West B, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G. Discovery of a novel selective inhibitor of oncogenic B-Raf kinase with potent anti-melanoma activity. Proc Nat Acad Sc U S A. 2008;26:3041-3049. PMID18287029 (PMC2268581)
  11. Lee J, Li L, Brafford P, Sproesser K, Haass N, Smalley K, van den Eijnden M, Halloran M, Tsai J, Bollag G, Herlyn M. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibitrs V600E-positive melanomas. Pig Cell Mel Res. 2010;23:820-827. PMID20973932
  12. John JK, Paraiso KHT, Rebecca VW, Cantini LP, Abel EV, Pagano N, Meggers E, Mathew R, Krepler C, Izumi V, Fang B, Koomen JM, Messina JL, Herlyn M, Smalley KSM. GSK3fl inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation. J Invest Dermatol. 2012;132:2818-2827. PMID22810307 (PMC3479306)
  13. Krepler C, Chunduru SK, Halloran MB, He X, Xiao M, Vultur A, Villanueva J, Mitsuuchi Y, Neiman EM, Benetatos C, Nathanson KL, Amaravadi RK, Pehamberger H, McKinlay M, Herlyn M. The novel SMAC inhibitor birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res. 2013;19:1784-1794. PMID23403634 (PMC3618595)
  14. Therapy resistance Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, Kˆrbel C, Laschke MW, Gimotty PA, Philipp SE, Krause E, P‰told S, Villanueva J, Krepler C, Fukunaga-Kalabis M, Hoth M, Bastian B, Vogt T, Herlyn M. Overcoming intrinsic multi-drug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell. 2013;23:811-825. PMID23764003 (PMC3810180)
  15. Villanueva J, Infante J, Krepler C, Reyes-Uribe P, Samanta M, Chen H-Y, Li B, Swoboda R, Wilson M, Vultur A, Fukunaga-Kalabis M, Wubbenhorst B, Chen TY, Liu Q, Sproesser K, DeMarini D, Gilmer T, Martin A-M, Marmorstein R, Schultz D, Speicher D, Karakousis G, Xu W, Amaravadi R, Xu X, Schuchter L, Herlyn M, Nathanson K. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Reports. 2013;4:1090-1099. PMID24055054
  16. Vultur A, Villanueva J, Krepler C, Rajan G, Chen Q, Li L, Gimotty P, Wilson M, Hayden J, Keeney F, Nathanson KL, Herlyn M. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene. 2014;33:1850-1861. PMID23624919 (PMC3769503)
  17. Ravindran Menon D, Das S, Krepler C, Vultur A, Rinner B, Schauer S, Kashofer K, Wagner K, Zhang G, Rad BE, Hass N, Soyer P, Gabrielli B, Somasundaram R, Hoefler G, Herlyn M, Schaider H. A stress-induced early innate response causes multi-drug tolerance in melanoma. Oncogene. 26 Nov 2014 [Epub ahead of print]. PMID25619837
  18. Stem cells and cancer Fang D, Leishear K, Nguyen TK, Finko R, Cai K, Fukunaga M, Li L, Brafford PA, Kulp AN, Xu X, Smalley KS, Herlyn M. Defining the conditions for the generation of melanocytes from human embryonic stem cells. Stem Cells. 2006;24:1668-1677. PMID16574754
  19. Zabierowski SE, Baubet V, Himes B, Li L, Fukunaga-Kalabis M, Patel S, McDaid R, Guerra M, Gimotty P, Dahmane N, Herlyn M. Direct reprogramming of melanocytes to neural crest stem-like cells by one defined factor. Stem Cells. 2011;1752-62. PMID21948558 (PMC3615703)
  20. FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest ARÖHerlyn M…Hayashizaki Y. A promoter-level mammalian expression atlas. Nature. 2014;507:462-70. PMID24670764
  21. Arner E, Daub CO…Herlyn M…Hayashizaki Y. Gene regulation; transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science. 2015;347:1010-1014. PMID25678556