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Development of a human three-dimensional organotypic skin-melanoma spheroid model for in vitro drug testing
Open accessAbstract
Despite remarkable efforts, metastatic melanoma (MM) still presents with significant mortality. Recently, mono-chemotherapies are increasingly replenished by more cancer-specific combination therapies involving death ligands and drugs interfering with cell signaling. Still, MM remains a fatal disease because tumors rapidly develop resistance to novel therapies thereby regaining tumorigenic capacity. Although genetically engineered mouse models for MM have been developed, at present no model is available that reliably mimics the human disease and is suitable for studying mechanisms of therapeutic obstacles including cell death resistance. To improve the increasing requests on new therapeutic alternatives, reliable human screening models are demanded that translate the findings from basic cellular research into clinical applications. By developing an organotypic full skin equivalent, harboring melanoma tumor spheroids of defined sizes we have invented a cell-based model that recapitulates both the 3D organization and multicellular complexity of an organ/tumor in vivo but at the same time accommodates systematic experimental intervention. By extending our previous findings on melanoma cell sensitization toward TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by co-application of sublethal doses of ultraviolet-B radiation (UVB) or cisplatin, we show significant differences in the therapeutical outcome to exist between regular two-dimensional (2D) and complex in vivo-like 3D models. Of note, while both treatment combinations killed the same cancer cell lines in 2D culture, skin equivalent-embedded melanoma spheroids are potently killed by TRAIL+cisplatin treatment but remain almost unaffected by the TRAIL+UVB combination. Consequently, we have established an organotypic human skin-melanoma model that will facilitate efforts to improve therapeutic outcomes for malignant melanoma by providing a platform for the investigation of cytotoxic treatments and tailored therapies in a more physiological setting.
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“In melanoma spheroids, for example, fibroblasts have been shown to accumulate in low-oxygen regions and upregulate genes associated with ECM production and wound response [288].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [288]
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Cites
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Method
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“Today, models are available not only to address effects induced by topical application of cosmetics, for example, but also skin changes arising from topical as well as systemic application of drugs to healthy [86,87] as well as diseased tissue [88].”
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In vitro models for evaluating safety and efficacy of novel technologies for skin drug delivery
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Cell Spheroids with Enhanced Aggressiveness to Mimic Human Liver Cancer In Vitro and In Vivo
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“SBCL2 (RGP) and WM-115 (VGP) 451-LU (MM) cells, was designed to mimic in vivo tumour environment and showed in vivo-like responses (Vorsmann et al., 2013).”
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“In melanoma spheroids, for example, fibroblasts have been shown to accumulate in low-oxygen regions and upregulate genes associated with ECM production and wound response [288].”
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Impedance Spectroscopy for the Non-Destructive Evaluation of In Vitro Epidermal Models
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“logical research ranging from melanoma research (6), the assessment of skin corrosion (7,8), skin irritation (9,10), and the penetration of chemical agents (11).”
BackgroundThe Effect of Lycopene Preexposure on UV‐B‐Irradiated Human Keratinocytes
Ascenso, A., Pedrosa, T., Pinho, S., Pinho, F., Oliveira, J. M. P. F. D., Cabral Marques, H., Oliveira, H., Simões, S., & Santos, C. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/8214631 · Cited by 57
Cho, W., Ahn, M., Kim, B. S., & Cho, D. (2022) · Advanced Science · doi:10.1002/advs.202202093 · Cited by 56
Spontaneously-forming spheroids as anin vitrocancer cell model for anticancer drug screening
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“Such 3D organotypic skin-bearing melanoma spheroids have been useful to investigate anticancer drugs in an environment that recreates a major part of the complexity of the tumor [186, 188].”
Background3D biofabrication of diseased human skin models in vitro
Ahn, M., Cho, W.-W., Park, W., Lee, J., Choi, M.-J., Gao, Q., Gao, G., Cho, D., & Kim, B. S. (2023) · Biomaterials Research · doi:10.1186/s40824-023-00415-5 · Cited by 57
“Using this model, Vörsmann et al. evaluated the sensitivity of melanoma cells to a tumor necrosis factor-related apoptosis-inducing ligand when ultraviolet B and cisplatin were applied simultaneously [57].”
MethodProgress in melanoma modelling in vitro
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“Melanoma is one of the most aggressive types of human cancers, and its lifetime risk and mortality rates have been steadily increasing for decades.(41,42) In addition, melanomas are exceptionally resistant to chemotherapy treatment and have a high incidence of relapse.”
BackgroundTRAIL-Mediated Apoptosis in Breast Cancer Cells Cultured as 3D Spheroids
Chandrasekaran, S., Marshall, J. R., Messing, J., Hsu, J., & King, M. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111487 · Cited by 50
Immune-competent human skin disease models
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A 3D Organotypic Melanoma Spheroid Skin Model
Müller, I., & Kulms, D. (2018) · Journal of Visualized Experiments · doi:10.3791/57500 · Cited by 50
“This figure has been taken from Voersmann et al.(15) with permission.”
MethodInfluentialOrganotypic 3D Models of the Ovarian Cancer Tumor Microenvironment
Watters, K. M., Bajwa, P., & Kenny, H. A. (2018) · Cancers · doi:10.3390/cancers10080265 · Cited by 49
Non-animal models in dermatological research
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Niessner, H., Sinnberg, T., Kosnopfel, C., Smalley, K., Beck, D., Praetorius, C., Mai, M., Beissert, S., Kulms, D., Schaller, M., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0098 · Cited by 42
“Melanoma spheroids were generated and prepared via the "hanging drop" method as described previously (19).”
MethodAnti-Cancer Drug Validation: the Contribution of Tissue Engineered Models
Carvalho, M. R., Lima, D., Reis, R. L., Oliveira, J. M., & Correlo, V. M. (2017) · Stem Cell Reviews and Reports · doi:10.1007/s12015-017-9720-x · Cited by 45
The renaissance of human skin organ culture: A critical reappraisal
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Saltari, A., Truzzi, F., Quadri, M., Lotti, R., Palazzo, E., Grisendi, G., Tiso, N., Marconi, A., & Pincelli, C. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.05.116 · Cited by 40
“Skin reconstructs are a good tool for studying tumor-microenvironment interactions (Vo¨rsmann et al., 2013).”
MethodCalcium phosphate nanoparticle-mediated transfection in 2D and 3D mono- and co-culture cell models
Sokolova, V., Rojas‐Sánchez, L., Białas, N., Schulze, N., & Epple, M. (2018) · Acta Biomaterialia · doi:10.1016/j.actbio.2018.11.051 · Cited by 43
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3D melanoma spheroid model for the development of positronium biomarkers
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The Melding of Drug Screening Platforms for Melanoma
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Full-Thickness Human Skin Equivalent Models of Atopic Dermatitis
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“Data from 3D cultures can more closely mimic the clinical setting, and this justifies their employment [26].”
BackgroundGoncalves, K., Gomez, P. D. L. S., Costello, L., Smith, L. A., Mead, H., Simpson, A., & Przyborski, S. A. (2022) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10415 · Cited by 30
A 3-D cell culture system to study epithelia functions using microcarriers
Jakob, P., Kehrer, J., Flood, P. F., Wiegel, C., Haselmann, U., Meissner, M., Stelzer, E. H. K., & Reynaud, E. G. (2016) · Cytotechnology · doi:10.1007/s10616-015-9935-0 · Cited by 29
“However, cysts are closed structures with an internalized lumen that do not allow access to the apical membrane for manipulation (infection, transfection and microinjection), and spheroids are disorganized cell aggregates that lack the structure necessary to mimic healthy in vivo tissue (Vörsmann et al. 2013).”
Advances in, and prospects of, 3D preclinical models for skin drug discovery
Imran, M., Moyle, P. M., Kamato, D., & Mohammed, Y. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.104208 · Cited by 30
In Vitro Three-Dimensional (3D) Models for Melanoma Immunotherapy
Nomdedeu‐Sancho, G., Gorkun, A. A., Mahajan, N., Willson, K., Schaaf, C. R., Votanopoulos, K. I., Atala, A., & Söker, S. (2023) · Cancers · doi:10.3390/cancers15245779 · Cited by 27
“Because the primary biopsy of melanoma is heterogeneous and contains different cell types, the addition of the melanoma cells into the hPSkCs as pre-assembled multicellular tumor organoids can standardize the contribution of each cell type to the model [24,25].”
BackgroundOsrodek, M., Hartman, M. L., & Czyż, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174203 · Cited by 27
“These include three-dimensional matrices [1,2], co-cultures with other cell types [3,4] and modifications of culture media supplementation [5–8].”
Developing strategies to predict photodynamic therapy outcome: the role of melanoma microenvironment
Vera, R. E., Lamberti, M. J., Rivarola, V. A., & Vittar, N. B. R. (2015) · Tumor Biology · doi:10.1007/s13277-015-4059-x · Cited by 25
Melanocytes in regenerative medicine applications and disease modeling
Coutant, K., Magne, B., Ferland, K., Fuentes-Rodriguez, A., Chancy, O., Mitchell, A., Germain, L., & Landreville, S. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05113-x · Cited by 24
“In their study, Vörs-mann and colleagues used both reconstructed skin and spheroids made with melanoma cell lines with different genetic backgrounds to recreate the melanoma microenvironment [165].”
BackgroundInfluentialCulturing Uveal Melanoma Cells
Angi, M., Versluis, M., & Kalirai, H. (2015) · Ocular Oncology and Pathology · doi:10.1159/000370150 · Cited by 24
Li, M., Song, X., Jin, S., & Ye, K. (2021) · Bio-Design and Manufacturing · doi:10.1007/s42242-021-00134-7 · Cited by 24
3D Bioprinting: An Enabling Technology to Understand Melanoma
Fernandes, S., Vyas, C., Lim, P., Pereira, R. F., Virós, A., & Bártolo, P. (2022) · Cancers · doi:10.3390/cancers14143535 · Cited by 25
Herrera-Martínez, A. D., van den Dungen, R., Dogan, F., van Koetsveld, P. M., Culler, M. D., de Herder, W. W., Luque, R. M., Feelders, R. A., & Hofland, L. J. (2019) · Endocrine Related Cancer · doi:10.1530/erc-19-0086 · Cited by 23
Animals Used in Research and Education, 1966–2016: Evolving Attitudes, Policies, and Relationships
Lairmore, M. D., & Ilkiw, J. E. (2015) · Journal of Veterinary Medical Education · doi:10.3138/jvme.0615-087r · Cited by 25
Vetma, V., Guttà, C., Peters, N., Praetorius, C., Hutt, M., Seifert, O., Meier, F. E., Kontermann, R. E., Kulms, D., & Rehm, M. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0512-5 · Cited by 24
Srisongkram, T., Weerapreeyakul, N., & Thumanu, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114141 · Cited by 23
“The 3D melanoma culture system was introduced in three different ways, including (i) multicellular melanoma spheroids, multicellular melanoma spheroids in skin equivalent model [29], and skin or melanoma on chip [30].”
MethodMelanoma spheroid-containing artificial dermis as an alternative approach to in vivo models
Mônico, D. A., Calori, I. R., Souza, C., Espreáfico, E. M., Bi, H., & Tedesco, A. C. (2022) · Experimental Cell Research · doi:10.1016/j.yexcr.2022.113207 · Cited by 21
A scaffold-free surface culture of B16F10 murine melanoma cells based on magnetic levitation
Jeong, Y. G., Lee, J. S., Shim, J. K., & Hur, W. (2016) · Cytotechnology · doi:10.1007/s10616-016-0026-7 · Cited by 19
“2005) and to construct an organotypic skin melanoma model for in vitro drug testing (Vörsmann et al. 2013).”
MethodTowards an advanced cell-based in vitro glioma model system
Mikhailova, V., Gulaia, V. S., Tiasto, V., Александрович, Р. С., Yatsunskaya, M., & Kagansky, A. (2018) · Global Medical Genetics · doi:10.3934/genet.2018.2.91 · Cited by 18
From simplicity to complexity in current melanoma models
Michielon, E., de Gruijl, T. D., & Gibbs, S. (2022) · Experimental Dermatology · doi:10.1111/exd.14675 · Cited by 18
Michielon, E., González, M. L., Stolk, D. A., Stolwijk, J. G. C., Roffel, S., Waaijman, T., Lougheed, S. M., de Gruijl, T. D., & Gibbs, S. (2023) · Cancers · doi:10.3390/cancers15102849 · Cited by 17
Computational models of melanoma
Albrecht, M., Lucarelli, P., Kulms, D., & Sauter, T. (2020) · Theoretical Biology and Medical Modelling · doi:10.1186/s12976-020-00126-7 · Cited by 17
“Fully functional organotypic skin constructs [123] can mimic all melanoma progression stages.”
BackgroundBridging scales in cancer progression: Mapping genotype to phenotype using neural networks
Gerlee, P., Kim, E., & Anderson, A. R. A. (2014) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2014.04.013 · Cited by 17
“with the development of organotypic cultures that represent a caricature of the real system containing not only cancer cells but also stromal cells (51, 52, 53) and ex vivo assays (54, 55) that can keep a slice of real tissue alive for some time.”
BackgroundLange, J., Weil, F., Riegler, C., Groeber, F., Rebhan, S., Kurdyn, S., Alb, M., Kneitz, H., Gelbrich, G., Walles, H., et al. (2016) · Biotechnology Journal · doi:10.1002/biot.201600360 · Cited by 16
“Currently, artificial human skin models are used as a test platform for cosmetic, pharmacological, immunological, pathological and microbiological in vitro studies [2-5].”
BackgroundMistro, G. D., Riemann, S., Schindler, S., Beissert, S., Kontermann, R. E., Ginolhac, A., Halder, R., Presta, L., Sinkkonen, L., Sauter, T., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04502-8 · Cited by 15
“3D melanoma spheroids Melanoma spheroids were generated using the “hanging drop” method [24].”
BackgroundMethodA preclinical model of cutaneous melanoma based on reconstructed human epidermis
Leikeim, A., Wußmann, M., Schmidt, F. F., Neto, N. G. B., Benz, F., Tiltmann, K., Junger, C., Monaghan, M. G., Schilling, B., & Groeber-Becker, F. K. (2022) · Scientific Reports · doi:10.1038/s41598-022-19307-0 · Cited by 17
Chen, H., Wei, X., Chen, H., Wei, H., Wang, Y., Nan, W., Zhang, Q., & Wen, X. (2019) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2018.1544142 · Cited by 15
Generation of 3D melanoma models using an assembloid-based approach
Rodrigues, D. B., Moreira, H. R., Jarnalo, M., Horta, R., Marques, A. P., Reis, R. L., & Pirraco, R. P. (2024) · Acta Biomaterialia · doi:10.1016/j.actbio.2024.02.023 · Cited by 14
ReBiA—Robotic Enabled Biological Automation: 3D Epithelial Tissue Production
Königer, L., Malkmus, C., Mahdy, D., Däullary, T., Götz, S., Schwarz, T., Gensler, M., Pallmann, N., Cheufou, D. H., Rosenwald, A., et al. (2024) · Advanced Science · doi:10.1002/advs.202406608 · Cited by 14
Fucina, G., Cesca, K., Berti, F. V., Biavatti, M. W., & Porto, L. M. (2022) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2022.130183 · Cited by 13
Characterization of human melanoma skin cancer models: A step towards model-based melanoma research
Daugaard, N. D., Tholstrup, R., Tornby, J. R., Bendixen, S. M., Larsen, F. T., Zio, D. D., Barnkob, M. B., Ravnskjær, K., & Brewer, J. R. (2024) · Acta Biomaterialia · doi:10.1016/j.actbio.2024.11.018 · Cited by 13
Modeling Skin Inflammation Using Human In Vitro Models
Boarder, E., Rumberger, B., & Howell, M. D. (2021) · Current Protocols · doi:10.1002/cpz1.72 · Cited by 12
Commandeur, S., SPARKS, S. J., Chan, H. L., Gao, L. Y., Out‐Luiting, J. J., Gruis, N. A., van Doorn, R., & Ghalbzouri, A. E. (2014) · Melanoma Research · doi:10.1097/cmr.0000000000000079 · Cited by 13
Liposomal fusion of plant-based extracellular vesicles to enhance skin anti-inflammation
Ryu, J. S., Park, H. S., Kim, M. J., Lee, J.-S., Jeong, E. Y., Cho, H., Kim, S., Seo, J. Y., Cho, H. D., Kang, H. C., et al. (2024) · Journal of Industrial and Engineering Chemistry · doi:10.1016/j.jiec.2024.09.038 · Cited by 15
Recreating Human Skin In Vitro: Should the Microbiota Be Taken into Account?
Galvan, A., Pellicciari, C., & Calderan, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021165 · Cited by 11
Kaczmarek, K., Wieckiewicz, J., Węglarczyk, K., Siedlar, M., & Baran, J. (2021) · Cancers · doi:10.3390/cancers13123004 · Cited by 11
“showed resistance of melanoma cell spheroids to TRAIL, while the same cells grown in a monolayer were sensitive to TRAIL-induced apoptosis [63].”
BackgroundAngeli, C., Wróblewska, J. P., Klein, E., Margue, C., & Kreis, S. (2024) · STAR Protocols · doi:10.1016/j.xpro.2024.103058 · Cited by 10
Metadata
- Authors
- Vörsmann, H., Groeber, F., Walles, H., Busch, S., Beissert, S., Walczak, H., & Kulms, D.
- Affiliations
- University of Stuttgart (DE)
- Fraunhofer Institute for Interfacial Engineering and Biotechnology (DE)
- Technische Universität Dresden (DE)
- University College London (GB)
- Corresponding author
- Kulms, D
- Venue
- Cell Death & Disease
- Published
- 2013-07-11
- Volume
- 4
- Issue
- 7
- Pages
- e719-e719
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3730422
- OpenAlex
- W2042222655
- Cited by
- 168
- References
- 44
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 14 · 2023: 8 · 2022: 18 · 2021: 12 · 2020: 15 · 2019: 14 · 2018: 16 · 2017: 14 · 2016: 16 · 2015: 13 · 2014: 11 · 2013: 1
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- Funders
- Deutsche Krebshilfe
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- metastatic melanoma, 3D tumor models, TRAIL sensitization, cisplatin, UV-B radiation, combination therapy, drug resistance, in vitro drug testing, tumor necrosis factor-related apoptosis-inducing ligand
- MeSH terms
- Antineoplastic Agents, Cisplatin, Drug Screening Assays, Antitumor, Drug Synergism, Humans, Melanoma, Skin Neoplasms, Skin, Artificial, Spheroids, Cellular, Coculture Techniques, Cell Line, Tumor, TNF-Related Apoptosis-Inducing Ligand
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