The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
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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Citations
Cites
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MethodABCB5-Mediated Doxorubicin Transport and Chemoresistance in Human Malignant Melanoma
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“Recombinant human iz-TRAIL protein was prepared as previously described.(41) Cisplatin was obtained from Platinex (Bristol, UK).”
MethodKeilholz, U., Goey, S. H., Punt, C. J. A., Proebstle, T. M., Salzmann, R., Scheibenbogen, C., Schadendorf, D., Liénard, D., Enk, A., Dummer, R., et al. (1997) · Journal of Clinical Oncology · doi:10.1200/jco.1997.15.7.2579 · Cited by 193
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“Given the need for better suitable in vitro test systems, we have generated a full thickness organotypic human skin model that displays a differentiation status homologous to normal human skin.(30) Aiming to decode the molecular mechanisms decisive for melanoma resistance, we took advantage of large and differentiated…”
BackgroundGrowth and Cellular Characteristics of Multicell Spheroids
Sutherland, R. M., & Durand, R. E. (1984) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-642-82340-4_2 · Cited by 166 · cited 1×
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MethodMelanoma Stem Cells: The Dark Seed of Melanoma
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BackgroundTreatment for metastatic malignant melanoma: Old drugs and new strategies
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“Successful treatment of melanoma is particularly impaired by the fact that metastatic disease quickly becomes resistant to chemotherapy and combination therapies, respectively.(19,20) Two proteins have recently been shown to confer chemoresistance specifically to melanoma cells: the ATP-dependent drug efflux transport…”
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“tools for novel therapeutic approaches, especially 3D models that contain human MM cells.(12) However, most current models are limited to the dermal compartment of the skin that contains MM nests consisting of only few cells and therefore do not adequately recapitulate melanoma metastases.”
BackgroundSmac mimetics as new cancer therapeutics
Chen, D. J., & Huerta, S. (2009) · Anti-Cancer Drugs · doi:10.1097/cad.0b013e32832ced78 · Cited by 113
TRAIL and Other TRAIL Receptor Agonists as Novel Cancer Therapeutics
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“Two proteins have recently been shown to confer chemoresistance specifically to melanoma cells: the ATP-dependent drug efflux transporter ABCB5(21,22) and JARID1B, a histone H3 demethylase that slows down the cell cycle.(23,24) Comparing the expression levels of ABCB5 and JARID1B in melanoma spheroids with primary cut…”
BackgroundHornle, M., Peters, N., Thayaparasingham, B., Vörsmann, H., Kashkar, H., & Kulms, D. (2010) · Oncogene · doi:10.1038/onc.2010.434 · Cited by 78 · cited 3×
“Irradiation with sublethal ultraviolet-B radiation (UVB) synergistically rendered them TRAIL sensitive by a mechanism involving caspase-3dependent cleavage of the X-linked inhibitor of apoptosis protein (XIAP).(13,14) Here, we find a similar, albeit less pronounced cisplatin-mediated TRAIL sensitization of melanoma ce…”
BackgroundInfluentialBortezomib Combination Therapy in Multiple Myeloma
Kapoor, P., Ramakrishnan, V. G., & Rajkumar, S. V. (2012) · Seminars in Hematology · doi:10.1053/j.seminhematol.2012.04.010 · Cited by 77
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“Furthermore, cisplatin is known to sensitize cancer cells from tissues of various origins to TRAIL-induced apoptosis.(27,28) When used at clinically achievable concentrations, cisplatin sensitized resistant melanoma cells representing the three major progression stages SBCL2 (RGP), WM-115 (VGP) and 451-LU (MM) to TRAI…”
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Chen, C.-S. J., Lavker, R. M., Rodeck, U., Risse, B. C., & Jensen, P. J. (1995) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12613595 · Cited by 51
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Human cutaneous malignant melanoma as a model for cancer
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20 Years After – Milestones in Molecular Photobiology
Kulms, D., & Schwarz, T. (2002) · Journal of Investigative Dermatology Symposium Proceedings · doi:10.1046/j.1523-1747.2002.19638.x · Cited by 22 · cited 3×
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BackgroundInfluentialRandomized, double‐blind, placebo‐controlled trial of sulindac in individuals at risk for melanoma
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“Keratinocytes were prepared from the epidermis and fibroblasts form the dermis of juvenile human foreskin,(39) Melanocytes were prepared from adult skin.(40) Keratinocytes were maintained in KGM 2 (PromoCell, Heidelberg, Germany), passaged at 50–70% confluency and used at passage four.”
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3D tumor spheroids: an overview on the tools and techniques used for their analysis
Costa, E. C., Moreira, A. F., de Melo-Diogo, D., Gaspar, V. M., Carvalho, M. P., & Correia, I. J. (2016) · Biotechnology Advances · doi:10.1016/j.biotechadv.2016.11.002 · Cited by 929
Matrigel: From discovery and ECM mimicry to assays and models for cancer research
Benton, G., Arnaoutova, I., George, J., Kleinman, H. K., & Koblinski, J. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.06.005 · Cited by 477
Skin models for the testing of transdermal drugs
Abd, E., Yousuf, S. A., Pastore, M. N., Telaprolu, K. C., Mohammed, Y., Namjoshi, S., Grice, J. E., & Roberts, M. S. (2016) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s64788 · Cited by 430
“Using combination therapies, Vörsmann et al 118 showed significant advantages in using their 3-”
Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines
Henry, C. M., Sullivan, G. P., Clancy, D. M., Afonina, I. S., Kulms, D., & Martin, S. J. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.072 · Cited by 330
“Active IL-36 Perturbs Differentiation in a 3D Organotypic Skin Model To explore the biological effects of active IL-36 in a more physiologically relevant setting, we utilized a well established model of reconstituted human skin with primary keratinocytes and dermal fibroblasts (Vörsmann et al., 2013).”
MethodThe use of skin models in drug development
Mathes, S. H., Ruffner, H., & Graf‐Hausner, U. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2013.12.006 · Cited by 328
“and UVB or cisplatin [112]”
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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