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

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

  • Caspar Wistar Professor in Melanoma Research
  • Director, The Wistar Institute Melanoma Research Center
  • Professor, Molecular and Cellular Oncogenesis Program
  • 215-898-3950, Office
  • 215-898-0980, Fax
Summary

Dr. Meenhard Herlyn’s laboratory at The Wistar Institute focuses on the biology that underlies melanoma, the most aggressive form of skin cancer. His efforts have pioneered the use of the three-dimensional “artificial skin” cultures to study the behavior of both tumor and normal cells that sustain tumor growth, a system known as the tumor microenvironment. The Herlyn Laboratory has transformed the scientific understanding of stem cells as they relate to cancer, and their work on the networks of signaling pathways in melanoma has formed the basis of numerous therapies now in clinical trials or very recently approved.

Born and educated in Germany, Dr. Herlyn received his D.V.M. at the University of Veterinary Medicine, Hanover in 1970 and went on to receive a D.Sc. in medical microbiology at the University of Munich in 1976. He came to The Wistar Institute as an associate scientist in 1976, where he worked in the emerging field of monoclonal antibodies, a technology that formed the basis of a portion of today’s new targeted therapeutics. In 1981, Dr. Herlyn became an assistant professor and established a laboratory that is, today, one the largest and best-known research groups on the study of melanoma biology.

The ability to model the microenvironment of normal and diseased human tissue through 3-D artificial skin provides the Herlyn Laboratory with a unique insight into cancer research. 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 signaling between normal and malignant cells, tumor formation, and drug resistance. These models also make a unique testing ground for ideas on future therapeutics and drug combinations.

The Herlyn Laboratory also seeks to further define the various signaling pathways that work in cancer cells in order to discover new opportunities to inhibit cancer growth through targeted therapeutics. Since therapy is increasingly guided by the genetic aberrations in tumors, Dr. Herlyn and his colleagues are developing combinations of compounds that take into account the genetic signature of tumors, with the specific goal of individualized cancer therapy. Currently, the Herlyn Laboratory collaborates with pharmaceutical companies as well as academic chemists and structural biologists to select and further develop compounds for tumor inhibition. Tumor heterogeneity, i.e., the differences between cells within one tumor, among different tumor lesions of the same patient, or between patients even if the tumors are of similar genetic signatures, provides major challenges for future therapy. The laboratory is developing biological signatures of melanoma cells that take into account the various forms of heterogeneity.

Another major effort of the Herlyn Laboratory is the study of therapy resistance and tumor dormancy. 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 tumors to resist treatment. Dr. Herlyn’s working hypothesis is that defined tumor subpopulations are central to dormancy and drug resistance due to their slow turnover and their non-responsiveness to growth signals. His efforts seek to define how tumor cells escape dormancy for growth, invasion, and metastasis, and how to best develop strategies for therapy.

Dr. Meenhard Herlyn’s laboratory at The Wistar Institute focuses on the biology that underlies melanoma, the most aggressive form of skin cancer. His efforts have pioneered the use of the three-dimensional “artificial skin” cultures to study the behavior of both tumor and normal cells that sustain tumor growth, a system known as the tumor microenvironment. The Herlyn Laboratory has transformed the scientific understanding of stem cells as they relate to cancer, and their work on the networks of signaling pathways in melanoma has formed the basis of numerous therapies now in clinical trials or very recently approved.

Born and educated in Germany, Dr. Herlyn received his D.V.M. at the University of Veterinary Medicine, Hanover in 1970 and went on to receive a D.Sc. in medical microbiology at the University of Munich in 1976. He came to The Wistar Institute as an associate scientist in 1976, where he worked in the emerging field of monoclonal antibodies, a technology that formed the basis of a portion of today’s new targeted therapeutics. In 1981, Dr. Herlyn became an assistant professor and established a laboratory that is, today, one the largest and best-known research groups on the study of melanoma biology.

The ability to model the microenvironment of normal and diseased human tissue through 3-D artificial skin provides the Herlyn Laboratory with a unique insight into cancer research. 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 signaling between normal and malignant cells, tumor formation, and drug resistance. These models also make a unique testing ground for ideas on future therapeutics and drug combinations.

The Herlyn Laboratory also seeks to further define the various signaling pathways that work in cancer cells in order to discover new opportunities to inhibit cancer growth through targeted therapeutics. Since therapy is increasingly guided by the genetic aberrations in tumors, Dr. Herlyn and his colleagues are developing combinations of compounds that take into account the genetic signature of tumors, with the specific goal of individualized cancer therapy. Currently, the Herlyn Laboratory collaborates with pharmaceutical companies as well as academic chemists and structural biologists to select and further develop compounds for tumor inhibition. Tumor heterogeneity, i.e., the differences between cells within one tumor, among different tumor lesions of the same patient, or between patients even if the tumors are of similar genetic signatures, provides major challenges for future therapy. The laboratory is developing biological signatures of melanoma cells that take into account the various forms of heterogeneity.

Another major effort of the Herlyn Laboratory is the study of therapy resistance and tumor dormancy. 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 tumors to resist treatment. Dr. Herlyn’s working hypothesis is that defined tumor subpopulations are central to dormancy and drug resistance due to their slow turnover and their non-responsiveness to growth signals. His efforts seek to define how tumor cells escape dormancy for growth, invasion, and metastasis, and how to best develop strategies for therapy.

Selected Publications (2014-Present)

1. Wang T, Ge Y, Xiao M, Lopez-Coral A, Li L, Roesch A, Huang C, Alexander P, Vogt T, Xu X, Hwang W-T, Lieu M, Belser E, Liu R, Somasundaram R, Herlyn M, Kaufman RE. SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. J Invest Dermatol. 2014;134:1108-1118. PMID24157461

2. Wong GS, Lee JS, Park YY, Klein-Szanto AJ, Waldron TJ, Cukierman E, Herlyn M, 
Gimotty P, Nakagawa H, Rustgi AK. Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophagus tumor microenvironment. Oncogenesis. 2013;2:e59. PMID23917221 (PMC3759121)

3. O'Connell M, Marchbank K, Webster M, Valiga A, Kaur A, Vultur A, Li L, Herlyn M, Villanueva J, Liu Q, Yin X, Widura S, Nelson J, Ruiz N, Camilli T, Indig FE, Flaherty K, Wargo J, Frederick DT, Cooper Z, Nair S, Amaravadi R, Schuchter L, Karakousis G, Xu W, Xu X, Weeraratna AT. Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discovery. 2013;3:1378-93. PMID24104062

4. Nallet-Staub F, Marsaud V, Li L, Gilbert C, Dodier S, Bataille V, Sudol M, Herlyn M, Mauviel A. Pro-invasive activity of the hippo pathway effectors YAP and TAZ in cutaneous melanoma. J Invest Dermatol. 2014;134:123-132. PMID23897276

5. 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)

6. Ma X-H, Pioa S-F, Dey S, Mcafee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK. Targeting ER stress induced autophagy overcomes resistance to BRAF inhibition in melanoma. J Clin Invest. 2014;124:1406-1417. PMID24569374

7. FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassman T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, Bertin N, Jørgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva YA, Plessy C, Vitezic M, Severin J, Semple C, Ishizu Y, Young RS, Francescatto M, Alam I, Albanese D, Altschuler GM, Arakawa T, Archer JA, Arner P, Babina M, Rennie S, Balwierz PJ, Beckhouse AG, Pradhan-Bhatt S, Blake JA, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs AM, Califano A, Cannistraci CV, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers HC, Dalla E, Davis CA, Detmar M, Diehl AD, Dohi T, Drabløs F, Edge AS, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairbairn L, Fang H, Farach-Carson MC, Faulkner GJ, Favorov AV, Fisher ME, Frith MC, Fujita R, Fukuda S, Furlanello C, Furino M, Furusawa J, Geijtenbeek TB, Gibson AP, Gingeras T, Goldowitz D, Gough J, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Harbers M, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto T, Herlyn M, Hitchens KJ, Ho Sui SJ, Hofmann OM, Hoof I, Hori F, Huminiecki L, Iida K, Ikawa T, Jankovic BR, Jia H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kaiho A, Kajiyama K, Kanamori-Katayama M, Kasianov AS, Kasukawa T, Katayama S, Kato S, Kawaguchi S, Kawamoto H, Kawamura YI, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klinken SP, Knox AJ, Kojima M, Kojima S, Kondo N, Koseki H, Koyasu S, Krampitz S, Kubosaki A, Kwon AT, Laros JF, Lee W, Lennartsson A, Li K, Lilje B, Lipovich L, Mackay-Sim A, Manabe R, Mar JC, Marchand B, Mathelier A, Mejhert N, Meynert A, Mizuno Y, de Lima Morais DA, Morikawa H, Morimoto M, Moro K, Motakis E, Motohashi H, Mummery CL, Murata M, Nagao-Sato S, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nakazato K, van Nimwegen E, Ninomiya N, Nishiyori H, Noma S, Noma S, Noazaki T, Ogishima S, Ohkura N, Ohimiya H, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DA, Pain A, Passier R, Patrikakis M, Persson H, Piazza S, Prendergast JG, Rackham OJ, Ramilowski JA, Rashid M, Ravasi T, Rizzu P, Roncador M, Roy S, Rye MB, Saijyo E, Sajantila A, Saka A, Sakaguchi S, Sakai M, Sato H, Savvi S, Saxena A, Schneider C, Schultes EA, Schulze-Tanzil GG, Schwegmann A, Sengstag T, Sheng G, Shimoji H, Shimoni Y, Shin JW, Simon C, Sugiyama D, Sugiyama T, Suzuki M, Suzuki N, Swoboda RK, 't Hoen PA, Tagami M, Takahashi N, Takai J, Tanaka H, Tatsukawa H, Tatum Z, Thompson M, Toyodo H, Toyoda T, Valen E, van de Wetering M, van den Berg LM, Verado R, Vijayan D, Vorontsov IE, Wasserman WW, Watanabe S, Wells CA, Winteringham LN, Wolvetang E, Wood EJ, Yamaguchi Y, Yamamoto M, Yoneda M, Yonekura Y, Yoshida S, Zabierowski SE, Zhang PG, Zhao X, Zucchelli S, Summers KM, Suzuki H, Daub CO, Kawai J, Heutink P, Hide W, Freeman TC, Lenhard B, Bajic VB, Taylor MS, Makeev VJ, Sandelin A, Hume DA, Carninci P, Hayashizaki Y. A promoter-level mammalian expression atlas. Nature. 2014;507:462-70. PMID: 24670764

8. Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, Ntini E, Arner E, Valen E, Li K, Schwarzfischer L, Glatz D, Raithel J, Lilje B, Rapin N, Bagger FO, Jørgensen M, Andersen PR, Bertin N, Rackham O, Burroughs AM, Baillie JK, Ishizu Y, Shimizu Y, Furuhata E, Maeda S, Negishi Y, Mungall CJ, Meehan TF, Lassmann T, Itoh M, Kawaji H, Kondo N, Kawai J, Lennartsson A, Daub CO, Heutink P, Hume DA, Jensen TH, Suzuki H, Hayashizaki Y, Müller F; FANTOM Consortium (...Herlyn M...), Forrest AR, Carninci P, Rehli M, Sandelin A. An atlas of active enhancers across human cell types and tissues. Nature. 2014;507(7493):455-61. PMID24670763

9. Morikawa H, Ohkura N, Vandenbon A, Itoh M, Nagao-Sato S, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest AR, Standley, DM, Date H, Sakaguchi S; FANTOM Consortium (...Herlyn M...). Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc Natl Acad Sci USA. 2014;111:5289-5294. PMID24706905

10. Peng H, Talebzadeh-Farrooji M, Osborne MJ, Prokop JW, McDonald PC, Karar J, Hou Z, He M, Kebebew E, Orntoft T, Herlyn M, Caton AJ, Fredericks W, Malkowicz B, Paterno CS, Carolin AS, Speicher DW, Skordalakes E, Huang Q, Dedhar S, Borden KL, Rauscher FJ 3rd. LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase. Cancer Res. 2014;74:1390-1403. PMID24590809

11. Arner E, Forrest AR, Ehrlund A, Mejhert N, Itoh M, Kawaji H, Lassmann T, Laurencikiene J, Rydén M, Arner P, FANTOM Consortium (...Herlyn M...). Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells. PLoS One. 2014;9(3):e80274. PMID24676332

12. Hasegawa Y, Tang D, Takahashi N, Hayashizah Y, Forrest AR, FANTOM Consortium (…Herlyn M…), Suzuki H. CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes. Sci Rep. 2014;4:5228. PMID24957798

13. Yang R, Zhend Y, Li L, Liu S, Spata M, Wei Z, Nace A, Herlyn M, Cui R, Guo W, Cotsarelis G, Xu X. Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors. Nat Comm. 2014;5:5807. PMID25510211

14. Cierlitza M, Chauvistre H, Bogeski I, Zhang X, Hauschild A, Herlyn M, Schadendorf D, Vogt T, Roesch A. Mitochondiral oxidative stress as a novel therapeutic target to overcome intrinsic drug resistance in melanoma subpopulations. Exp Dermatol. 2015;24:155-157. PMID25453510

15. 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. 2014; Nov. 26 [Epub ahead of print]. PMID25619837

16. Kraya AA, Piao S, Xu X, Zhang G, Herlyn M, Gimotty P, Levine B, Amaravadi RK, Speicher DW. Identification of secreted proteins that reflect autophagy dynamics within tumor cells. Autophagy. 2015;11:60-74. PMID25484078

17. Webster MR, Xu M, Kinzler KA, Kaur A, Appleton J, O’Connell MP, Marchbank K, Valiga A, Dang VM, Perego M, Zhang G, Slipicevic A, Keeney F, Lehrmann E, Wood W 3rd, Becker KG, Kossenov AV, Frederick DT, Flaherty KT, Xu X, Herlyn M, Murphy ME, Weeraratna AT. Wnt5a promotes and adaptive, senescence-like stress stress response, while continuing to drive invasion in melanoma cells. Pigment Cell Melanoma Res. 2015; 28:184-195. PMID25407936

18. Arner E, Daub CO, Vitting-Seerup K, Andersson R, Lilje B, Drablos F, Lennartsson, A, Rönnerblad M, Hrydziuszko O, Vitezic M, Freeman TC, Alhendi A, Arner A, Axton R, Baillie JK, Beckhouse A, Bodega B, Briggs J, Brombacher F, Davis M, Detmar M, Ehrlund A, Endoh M, Eslami A, Fagiolini M, Fairbairn L, Faulkner GJ, Ferrai C, Fisher ME, Forrester L, Goldowitz D, Guler R, Ha T, Hara M, Herlyn M, Ikawa T, Kai C, Kawamoto H, Khachigian L, Klinken PS, Kojima S, Koseki H, Klein S, Mejhert N, Miyaguchi K, Mizuno Y, Morimoto M, Morris KJ, Mummery C, Nakachi Y, Ogishima S, Okada-Hatakeyama M, Okazaki Y, Orlando Y, Ovchinnikov D, Passier R, Patrikakis M, Pombo A, Qin XY, Roy S, Sato H, Savvi S, Saxena A, Schwegmann A, Sugiyama D, Swoboda R, Tanaka R, Tomoiu A, Winteringham LN, Wolvetang E, Yanagi-Mizuochi C, Yoneda M, Zabierowski S, Zhang P, Abugessaisa I, Bertin N, Diehl AD, Fukuda S, Furuno M, Harshbarger J, Hasegawa A, Hori F, Ishikawa-Kato S, Ishizu Y, Itoh M, Kawashima T, Kojima M, Kondo N, Lizio M, Meehan TF, Mungall CJ, Murata M, Nishiyori-Sueki H, Sahin S, Sato-Nagao S, Severin J, de Hoon MJL, Kawai J, Kasukawa T, Lassmann T, Suzuki H, Kawaji H, Summers KM, Wells C, Hume DA, Forrest ARR, Sandelin A, Carninci P, Hayashizaki Y. Gene regulation; transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science. 2015;347:1010-1014. PMID25678556

19. Wang T, Xiao M, Ge Y, Krepler C, Belser E, Lopez-Coral A, Xu X, Zhang G, Azuma R, Liu Q, Liu R, Li L, Amaravadi RK, Xu W, Karakousis G, Gangadhar TC, Schuchter LM, Lieu M, Khare S, Halloran MB, Herlyn, M, Kaufman, R. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin Cancer Res. Jan 23, 2015 [Epub ahead of print]. PMID25617424

20. Joshi S, Wels C, Beham-Schmid C, Fukunaga-Kalabis M, Holmen SL, Otte M, Herlyn M, Waldhoer M, Schaider H. Galpha(13) mediates human cytomegalovirus-encoded chemokine receptor US28 induced cell death in melanoma. Int J Cancer. March 6, 2015 [Epub ahead of print]. PMID25754407

21. 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. Feb. 23, 2015 [Epub ahead of print]. PMID25705850

22. Liang C; FANTOM Consortium [….Herlyn M….], Forrest AR, Wagner GP. The statistical geometry of transcriptome divergence in cell-type evolution and cancer. Nat Comm. 2015;6:6066. PMID: 25585899

23. Liu J, Fukunaga-Kalabis M, Li L, Herlyn M. Developmental pathways activated in melanocytes and melanoma. Arch Biochem Biophys. 2014;563C:13-21. PMID25109840

24. Schadendorf D, Fisher D, Garbe C, Gershenwald JE, Grob J-J, Halpern A, Herlyn M, Marchetti MA, McArthur G, Ribas A, Roesch A, Hauschild A. Melanoma. Nature Reviews, 2015, in press.