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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (15 December 2025) | Viewed by 5282

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Prof. Dr. Marilena Loizidou

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Guest Editor

Division of Surgery and Interventional Science, University College London, London, UK
Interests: 3D in vitro cancer models; tumouroids; targeted treatments; theranostics; nanotechnology; precision oncology; patient-derived 3D models
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Prof. Dr. Eirini Velliou

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Co-Guest Editor

Centre for 3D Models of Health and Disease, University College London (UCL), Charles Bell House, London, UK
Interests: cancer models; 3D models; fibrosis; matrix stiffness; pancreatic cancer; liver cancer; ovarian cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The focus of this Special Issue is to highlight novel research findings in multicellular 3D in vitro models of cancer. Multicellularity mimics the in vivo scenario and helps in developing relevant biomimetic models to investigate disease progression and test drugs. As highlighted by the FDA, 3D in vitro models hold great promise for low-cost animal-free testing.

We welcome research articles focused on developing complex models of the cancer microenvironment with a strong focus on multicellularity. We particularly encourage submissions on primary tissue work and the development of biomaterial-based animal-free models.

Prof. Dr. Marilena Loizidou
Prof. Dr. Eirini Velliou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

3D in vitro cancer models
multicellular cancer models
cancer microenvironment
tumour–stroma interactions

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Published Papers (3 papers)

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19 pages, 3076 KB

Open AccessArticle

Dissecting Context-Specific Effects of ERK5 Signaling in Triple-Negative Breast Cancer

by Katherine L. Hebert, Sarah B. Knopf, Thomas Cheng, Megan C. Benz, Bridgette M. Collins-Burow, Jorge A. Belgodere, Frank H. Lau, Elizabeth C. Martin, Matthew E. Burow and Van H. Barnes

Cancers 2026, 18(3), 376; https://doi.org/10.3390/cancers18030376 - 26 Jan 2026

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Abstract

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of cancer with poor clinical outcomes. There is a critical need to identify novel, druggable targets for TNBC to improve therapy response and patient outcomes. Due to their roles in critical processes driving cancer progression, kinases have been a major focus of drug discovery efforts. The role of extracellular signal-regulated kinase 5 (ERK5) in mediating TNBC extracellular matrix (ECM) has previously been described in 2D culture and in vivo. Here, we characterized the impact of ERK5 on breast cancer biology in 2D culture, 3D spheroids, and our 3D breast adipose-macrophysiological system (BA-MaPS). Methods: We assessed migration changes in MDA-MB-231 parental and ERK5-knockout (ERK5-ko) cells cultured in the three in vitro models using transwell, scratch, and spheroid pseudo-migration assays. Differential gene expression among these cell lines in the three platforms was assessed by RNA sequencing and pathway analysis. Stromal remodeling of adipocytes and matrix was evaluated by H&E and Masson’s Trichrome. Results: Across the in vitro models, ERK5 deletion impaired TNBC cell migration. ERK5-mediated transcriptomic changes included genes associated with epithelial-to-mesenchymal transition (EMT) and migration, with further analysis showing significant alterations in core and associated matrisome. Histological staining corroborated the downregulation of collagen with ERK5 depletion in the BA-MaPS. The NFκB pathway was significantly upregulated only in the ERK5-ko 2D-cultured cells, not in 3D spheroids nor the BA-MaPS model. Conclusions: These results indicate a link between ERK5 and TNBC progression through regulation of TME remodeling, EMT, and cell motility. Differences in 2D culture, 3D spheroid, and BA-MaPS underscore the importance of using physiologically relevant models in breast cancer research. Full article

(This article belongs to the Special Issue Multicellular 3D Models of Cancer)

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16 pages, 6261 KB

Open AccessArticle

Spatial Organisation and Invasive Behaviour of Metastatic Cutaneous Squamous Cell Carcinoma-Derived Multicellular Spheroids Reflect Tumour Cell Phenotype

by Benjamin Genenger, Jessica Conley, Chelsea Penney, Luke McAlary, Jay R. Perry, Bruce Ashford and Marie Ranson

Cancers 2025, 17(21), 3399; https://doi.org/10.3390/cancers17213399 - 22 Oct 2025

Cited by 1 | Viewed by 798

Abstract

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy of the head and neck area, with a propensity to spread to local lymph nodes. Epithelial-to-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) play a well-documented role in the progression of the disease. In this study, we developed and characterised multicellular tumour spheroids (MCTS) composed of patient-derived metastatic cSCC cell lines—each exhibiting distinct phenotypes—combined with either dermal- or lymph node-derived fibroblasts. We aimed to investigate how these cellular combinations influence MCTS formation, spatial architecture, and invasive behaviour. We hypothesised that the interplay between different cSCC and fibroblast cell combinations would differentially influence spheroid formation and invasion. Methods: Using live-cell microscopy we assessed the spatial architectures specific to each cell line-fibroblast combination and evaluated the expression of EMT and CAF markers. Furthermore, we utilised MCTS in invasion models to investigate associations between the mode of invasion and the EMT phenotype of the cancer cell line. Results: We show that metastatic cSCC/fibroblast MCTS self-organise into distinct spatial architectures. They also invade through collagen in a manner influenced by fibroblasts but dominated by the EMT status of the originating cancer cells. Conclusions: These findings highlight the physiological relevance and utility of MCTS as models for investigating tumour–stroma interactions and invasion dynamics in metastatic cSCC. Full article

(This article belongs to the Special Issue Multicellular 3D Models of Cancer)

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22 pages, 58309 KB

Open AccessArticle

An Organoid Model for Translational Cancer Research Recapitulates Histoarchitecture and Molecular Hallmarks of Non-Small-Cell Lung Cancer

by Camilla T. Ekanger, Maria P. Ramnefjell, Maren S. F. Guttormsen, Joakim Hekland, Kristin Dahl-Michelsen, Maria L. Lotsberg, Ning Lu, Linda E. B. Stuhr, Laurence Hoareau, Pirjo-Riitta Salminen, Fabian Gärtner, Marianne Aanerud, Lars A. Akslen, James B. Lorens and Agnete S. T. Engelsen

Cancers 2025, 17(11), 1873; https://doi.org/10.3390/cancers17111873 - 3 Jun 2025

Cited by 3 | Viewed by 2973

Abstract

Background: Organoid cultures have received much attention in recent years due to the promise of patient-derived organoid cultures for exploration of personalized cancer treatment strategies. Organoid cultures have been established from a variety of malignancies; however, lack of a thorough histopathological analysis has limited the acceptance of organoid models as translational tools. Methods: Here, we aimed to establish patient-derived tumor-organoid (PDTO) models from human non-small-cell lung cancer (NSCLC) resection specimens and provide a thorough histopathological evaluation of the cultures. Results: We show that we were able to establish organoid cultures of lung adenocarcinomas (LUADs) and lung squamous cell carcinomas (LUSCs) successfully, and that the organoid cultures of different subtypes of NSCLC preserved the histoarchitecture and growth pattern of the tumors they derive from. Immunohistochemistry and AB-PAS staining confirmed the subtype-specific protein expression pattern and preserved mucin production in LUAD organoids. The genetic abnormalities of the tumors assessed by immunohistochemistry (IHC-P) were preserved in the organoid cultures. Conclusions: Our thorough study reveals conserved PDTO histopathology, supports further exploration, and encourages using PDTO models in translational research projects. PDTO models hold remarkable promise as patient-specific models and may be applied to predict therapy response in cases where molecular–pathological analyses pose significant management dilemmas, and they also may provide a platform for exploring the molecular mechanisms of therapy resistance in a biologically relevant model system. Full article

(This article belongs to the Special Issue Multicellular 3D Models of Cancer)

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