Molecular Dermatology
AG Schmidt
By combining modern genomic, cell biological, and translational approaches, we investigate disease mechanisms across multiple levels of biological organization, ranging from intracellular signaling pathways and changes in cellular states to complex interactions between distinct cell populations within tissues.
Melanoma Progression and Inflammatory Mechanisms
A major focus of our research is the identification of signaling networks that regulate melanoma progression and the development of therapy resistance. In parallel, we investigate vascular and immunological processes that control tissue homeostasis, immune cell recruitment, and allergic and inflammatory responses in the skin. Particular interest is devoted to understanding how skin-resident cells recognize environmental stimuli such as contact and drug allergens and initiate innate immune responses that shape subsequent adaptive inflammatory and allergic reactions.
Our overarching goal is to gain a better understanding of the molecular and cellular mechanisms that regulate inflammation, tissue homeostasis, and tumor progression in the skin. By integrating mechanistic basic research with translational approaches, we aim to identify novel molecular targets and develop innovative therapeutic strategies for patients suffering from inflammatory skin diseases and melanoma.
Methods and Technologies
To address these questions, we employ a broad range of molecular, cellular, and translational techniques. These include bulk, single-cell, and single-nucleus RNA sequencing from native and fixed tissues, engineered skin models, primary and immortalized cell cultures, Western blotting, quantitative RT-PCR (qRT-PCR), molecular cloning, CRISPR/Cas9-mediated genome editing, RNA interference (siRNA/shRNA), DNA profiling, lentiviral and retroviral gene transfer, chromatin immunoprecipitation (ChIP), promoter reporter assays, multicolor flow cytometry (FACS), immunofluorescence, immunohistochemistry, live-cell imaging, migration and invasion assays, as well as microfluidic flow simulation experiments.
Our research is organized into two major thematic areas:
Therapy Resistance and Cellular Plasticity in Melanoma
The introduction of immune checkpoint inhibitors, including anti-PD-1 and anti-CTLA-4 antibodies, as well as targeted therapies directed against the oncogenic RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway, has dramatically improved the treatment of advanced melanoma. However, durable clinical responses remain limited by the emergence of therapy resistance.
A major focus of our research is to understand how melanoma cells adapt to therapeutic stress and acquire resistance to both targeted therapies and immunotherapies. To address this challenge, we investigate the molecular programs that drive cellular plasticity, tumor adaptation, and disease progression, thereby limiting long-term therapeutic success.
Previous work from our laboratory identified the MEK5/ERK5 MAPK signaling pathway as an important mediator of melanoma progression and therapy resistance. Originally described as a stress-responsive and protective pathway in the vascular endothelium (see Contact Allergies, Inflammatory Mechanisms and Tissue Homeostasis), accumulating evidence suggests that melanoma cells can exploit MEK5/ERK5 signaling to cope with therapeutic stress and evade therapy-induced cell death and cell-cycle arrest (Figure 1).
Our current research investigates how the MEK5/ERK5 pathway and its downstream transcription factors KLF2 and KLF4 regulate melanoma cell proliferation, plasticity, and treatment response. Particular emphasis is placed on identifying transcriptional programs and cellular states associated with resistance to immunotherapies and targeted therapies. Using molecular, cellular, and preclinical models, we evaluate the therapeutic potential of targeting the MEK5/ERK5 pathway and its downstream networks. Our goal is to identify and exploit vulnerabilities associated with therapy resistance to improve the efficacy of existing and emerging treatments for patients with advanced melanoma.
Contact Allergies, Inflammatory Mechanisms, and Tissue Homeostasis
A long-standing focus of our research is the investigation of the molecular and cellular mechanisms that regulate contact and drug allergies as well as inflammatory tissue responses. We are particularly interested in how the innate immune system recognizes environmental stimuli and how signaling networks and cellular populations interact to maintain skin and vascular homeostasis.
Previous work from our laboratory demonstrated that certain contact and drug allergens activate components of the innate immune system. In particular, we identified Toll-like receptor 4 (TLR4) as a key sensor for the metal allergen nickel and established an important role for the NLRP3 inflammasome in inflammatory responses induced by several contact and drug allergens (Figure 2).
In addition, we investigate signaling networks that regulate the integrity and function of the vascular endothelium. Our studies identified the MEK5/ERK5/KLF2/KLF4 signaling cascade as a central protective pathway that mediates anti-inflammatory and vasoprotective functions and contributes to the maintenance of vascular homeostasis. Furthermore, our work suggests that ERK5-dependent signaling networks play important roles in the regulation of endothelial activation and inflammatory processes.
Current projects employ single-cell and single-nucleus transcriptomic approaches to better understand the heterogeneity and function of skin, immune, and endothelial cells, as well as their interactions in inflammatory and dermatological diseases. Our goal is to decipher the cellular and molecular networks that govern inflammation, tissue homeostasis, and disease progression.
Selected Publications
Paudel R, Goller S, Schwarz S, Meder K, Goebeler M, and Schmidt M (2026). AXL is a novel ERK5/KLF4 target in MEK inhibitor-treated melanoma. Neoplasia. 76:101301.
https://doi.org/10.1016/j.neo.2026.101301
Schmidt M, Knorz A, Meder K, Goller S, Imdahl F, Rocca Y, Goebeler M, and Khoueiry P (2026). Single Cell Analysis Reveals Dynamic Changes of Distinct Cell Populations in Human Nickel Allergy. Allergy. 81(4):1138-1148. https://doi.org/10.1111/all.70108
Paudel R, Goller S, Deutzmann F, Gillitzer A, Meder K, Knorz A, Schrama D, Goebeler M, and Schmidt M (2025). MEK5/ERK5 inhibition sensitizes NRAS-mutant melanoma to MAPK-targeted therapy by preventing Cyclin D/CDK4-mediated G1/S progression. Cell Death Dis. 16(1):689. https://doi.org/10.1038/s41419-025-08036-7
Frings, VG, Jopp L., Srivastava M., Presser D., Goebeler M., and Schmidt M (2022). Stress signalling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 36(12):2488-2498. https://doi.org/10.1111/jdv.18465
Adam C, Fusi L, Weiss, N, Goller, SG, Meder K., Frings, VG, Schmidt M (2020). Efficient suppression of NRAS-driven melanoma by co-inhibition of ERK1/2 and ERK5 MAPK pathways. J Invest Dermatol 140(12):2455-2465. https://doi.org/10.1016/j.jid.2020.03.972
Micosse C, von Meyenn L, Steck O, Kipfer E, Adam C, Simillion C, Schmidt M, Schlappbach C (2019) Human "TH9" cells are a subpopulation of PPAR-gamma(+) TH2 cells. Sci Immunol. 4(31). https://doi.org/10.1126/sciimmunol.aat5943
Adam, C, Wohlfarth, J, Haußmann, M, Sennefelder H, Rodin A, Maler M, Martin SF, Goebeler M, Schmidt M (2017). Allergy-inducing chromium compounds trigger potent innate immune stimulation via ROS-dependent inflammasome activation. J Invest Dermatol 137, 367–376. https://doi.org/10.1016/j.jid.2016.10.003
Komaravolu RK, Adam C, Moonen J-RAJ, Harmsen MC, Goebeler M, Schmidt, M (2015) Erk5 inhibits endothelial migration via KLF2-dependent down-regulation of PAK1. Cardiovascular Research 105, 86-95. https://doi.org/10.1093/cvr/cvu236
Raghavan, B, Martin SF, Esser PR, Goebeler M, Schmidt M (2012). Metal allergens Ni2+ and Co2+ facilitate hTLR4 homodimerization independently of hMD2. EMBO Reports 13, 109-15. https://doi.org/10.1038/embor.2012.155
Schmidt M, Raghavan B, Müller V, Vogl T, Fejer G, Tchaptchet S, Keck S, Kalis C, Nielsen PJ, Galanos C, Roth J, Skerra A, Martin SF, Freudenberg MA, Goebeler M (2010). Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 11, 814-819. https://doi.org/10.1038/ni.1919
Ohnesorge N, Viemann D, Schmidt N, Czymai T, Spiering D, Schmolke M, Ludwig S, Roth J, Goebeler M, Schmidt, M (2010). Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Krüppel-like factor 4 (KLF4). J Biol Chem 285, 26199-26210. https://doi.org/10.1074/jbc.M110.103127
Collaborations and Early-Career Researchers
Our research group is an international team that closely collaborates with other research groups at the University Hospital Würzburg and the Department of Dermatology, Venereology and Allergology. We welcome inquiries regarding research collaborations as well as applications from motivated bachelor's and master's students, and from doctoral candidates in the natural and medical sciences.
Contact
Prof. Dr. rer. nat. Marc Schmidt
E-Mail: schmidt_m11@ukw.de
Phone: +49 931 201 -26396