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Cancers
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3D Cultures and Organoids in Cancer Research
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3D Cultures and Organoids in Cancer Research

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (28 February 2026) | Viewed by 13520

Editors

Dr. Karla Rubio

E-Mail Website
Guest Editor
International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Instituto de Ciencias, Ecocampus, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla 72570, Mexico
Interests: the mechanisms of epigenetic regulation in cancer subtypes; lung diseases; neurodegenerative diseases and diseases associated with environmental pollution
Prof. Dr. César López-Camarillo

E-Mail Website
Guest Editor
Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX 03100, Mexico
Interests: microRNAs; lncRNAs; circRNAs; proteins; cancers; novel therapeutic targets; tumorigenesis; nutrigenomics; 3D cultures
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Three-dimensional (3D) cell cultures more accurately mimic the spatial architecture of tumors; therefore, they represent an innovative approach to discovering the complex biology of cancer. Moreover, recent advances in organoid technologies have enabled the construction of 3D models of patient-derived tumors in vitro. These models can better mimic tumor architecture, tumor microenvironment, and gene expression portraits. Three-dimensional cell cultures can better recapitulate the molecular features of in vivo tumor tissues, such as cell heterogeneity, oxygen and nutrient gradients, hypoxia grades, and the activation of oncogenic signaling pathways. Therefore, implementing reliable in vitro cancer 3D cultures containing cellular components of the stroma and extracellular matrix may provide information about its impact on the genetic programs leading to breast cancer development and progression. These characteristics significantly influence the reprogramming of non-coding RNAs’ and mRNAs' epigenetic and gene expression patterns. Three-dimensional cultures and organoids are a powerful tool in precision medicine and discovering new therapeutic targets. The advantages of 3D cultures include the ability to identify key genes and proteins that could be translated into developing novel therapeutic strategies.

This Special Issue aims to collate original research and review articles that cover recent advances in understanding the role of innovative 3D cell cultures and organoid models and their applications in elucidating the molecular mechanisms of cancer development and progression, drug screening, and personalized medicine.

This collection welcomes original research on the promises and challenges of 3D culture. Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • 3D cell cultures.
  • Organotypic 3D cultures.
  • 3D spheroids systems.
  • Induced pluripotent stem (iPS) cell-derived organoids.
  • Genome-wide profiling of non-coding RNAs in 3D cultures.
  • 3D cell cultures and organoid models for cancer stroma cells and the tumor microenvironment.

We look forward to receiving your contributions.

Dr. Karla Rubio
Prof. Dr. César López-Camarillo
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-anonymized 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 cell cultures
  • organotypic 3D cultures
  • 3D spheroids models
  • induced pluripotent stem (iPS)
  • organoids
  • tumoroids

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Published Papers (5 papers)

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Research

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17 pages, 5925 KB  
Article
Functional Precision Oncology in Fibrolamellar Carcinoma: Ex Vivo Identification of Therapeutic Vulnerabilities
by Sabina A. Schneider, Paulo D’Amora, Steven S. Evans, Paul Kent, Tom Stockwell, Vikrant S. Bakaya, Paula J. Bernard, Federico R. Francisco, Luisa Torres, John Henry, Jr., Ismael D. C. G. Silva and Robert A. Nagourney
Cancers 2026, 18(11), 1744; https://doi.org/10.3390/cancers18111744 - 27 May 2026
Viewed by 473
Abstract
Background: Fibrolamellar carcinoma (FLC) is a rare liver malignancy affecting adolescents. FLCs harbor a DNAJB1–PRKACA gene fusion that combines heat shock protein DNAJB1 with the catalytic subunit of protein kinase A. Surgery with systemic therapy provides 5-year survivals of 30–50%, but advanced disease [...] Read more.
Background: Fibrolamellar carcinoma (FLC) is a rare liver malignancy affecting adolescents. FLCs harbor a DNAJB1–PRKACA gene fusion that combines heat shock protein DNAJB1 with the catalytic subunit of protein kinase A. Surgery with systemic therapy provides 5-year survivals of 30–50%, but advanced disease remains largely incurable. Three-dimensional explants from 41 FLC patients were interrogated for drug sensitivity, resistance, and synergy against cytotoxics, targeted agents, and signal transduction inhibitors. Methods: Sterile specimens from histologically confirmed FLC patients were analyzed by Ex Vivo Analysis of Programmed Cell Death (EVA/PCD™) in a CLIA-licensed laboratory. Following mechanical and enzymatic disaggregation, explants underwent 72 h drug exposure. LC50 values were derived from five-point dose–response curves and compared with a database of over 10,000 human tumor analyses. Synergy was assessed by combination index. In parallel, targeted metabolomic profiling was performed in five FLC patients using tandem MS/MS. Results: Forty-one samples were analyzed. Of 24 drugs selected, tumor-cell yields were adequate for testing in 18 (75%). Single-agent activity favored vorinostat, followed by phenformin and 6-diazo-5-oxo-L-norleucine. Combinations favored gemcitabine plus oxaliplatin (GEMOX) and 5-FU plus interferon. Metabolomic analysis identified distinct signature consistent with mitochondrial dysfunction and altered polyamine metabolism. Conclusions: The present findings are exploratory, and hypothesis-generating and should not be interpreted as evidence of clinical efficacy. Prospective clinical validation and mechanistic studies will be required to further define the therapeutic relevance of these observations in fibrolamellar carcinoma. Full article
(This article belongs to the Special Issue 3D Cultures and Organoids in Cancer Research)
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25 pages, 7033 KB  
Article
In Vitro Model Characterizing Carcinogenic Progression of HPV-Positive Oropharyngeal Cancer
by Jesus Avila Tejeda, Sreejata Chatterjee and Craig Meyers
Cancers 2026, 18(4), 683; https://doi.org/10.3390/cancers18040683 - 19 Feb 2026
Viewed by 1124
Abstract
Background/Objective: Human papillomavirus (HPV) represents the most widespread sexually transmitted infection globally, with high-risk strains such as HPV16 driving a rising incidence of oropharyngeal squamous cell carcinoma (OPSCC), particularly in developed countries like the United States and United Kingdom. In the U.S., HPV16-associated [...] Read more.
Background/Objective: Human papillomavirus (HPV) represents the most widespread sexually transmitted infection globally, with high-risk strains such as HPV16 driving a rising incidence of oropharyngeal squamous cell carcinoma (OPSCC), particularly in developed countries like the United States and United Kingdom. In the U.S., HPV16-associated OPSCC has surpassed cervical cancer as the most common HPV-related malignancy. Despite the availability of preventive vaccines, uptake remains suboptimal among adolescents and shifting sexual behaviors have contributed to increased disease burden. Early detection remains a major clinical challenge due to the absence of defined precursor lesions and the extended latency between viral exposure and disease onset. Most patients present with advanced-stage disease and no prior clinical history of pre-malignancy, limiting access to early-stage samples and hindering biomarker discovery. Methods: To address these limitations, we developed an in vitro HPV16 oral cancer model, using the three-dimensional organotypic raft culture system that simulates the progression of HPV16-transfected oral epithelium from precancerous states to malignant phenotypes. Results: Using HPV16-transfected human tonsil keratinocytes, we generated stratified and differentiated epithelia that mimic the biochemical and structural changes observed in vivo. This system enables detailed monitoring of epithelial differentiation, biochemical shifts, viral genome status, and key oncogenic and metabolic markers associated with HPV16-driven OPSCC. By aligning expression profiles with clinical datasets, we validated the model through the measurement of virologic markers linked to infection and progression, as well as tissue markers indicative of carcinogenic transformation. Conclusions: This model offers a promising tool for refining early detection strategies and evaluating potential clinical biomarkers, ultimately aiming to improve diagnostic precision and therapeutic outcomes in HPV-associated OPSCC. Full article
(This article belongs to the Special Issue 3D Cultures and Organoids in Cancer Research)
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21 pages, 6153 KB  
Article
A Patient-Derived Organoid Platform from TUR-P Samples Enables Precision Drug Screening in Advanced Prostate Cancer
by Zaukir Bostan Ali, Mooktapa Plikomol, Tanan Bejrananda, Paramee Thongsuksai, Pokphon Khirilak, Natthapon Khongcharoen, Karan Ulhaka, Ratsamaporn Nontikarn, Onpawee Phanthuvet and Pasarat Khongkow
Cancers 2025, 17(24), 3973; https://doi.org/10.3390/cancers17243973 - 12 Dec 2025
Cited by 3 | Viewed by 1611
Abstract
Background: Patient-derived advanced prostate cancer organoids have been developed to mimic tumor heterogeneity and beneficially predict optimized drugs for specific patients. The organoids are promising functional drug screening models which can capture patient outcomes. However, organoid development from transurethral resection of the prostate [...] Read more.
Background: Patient-derived advanced prostate cancer organoids have been developed to mimic tumor heterogeneity and beneficially predict optimized drugs for specific patients. The organoids are promising functional drug screening models which can capture patient outcomes. However, organoid development from transurethral resection of the prostate (TUR-P) has been hampered by a low success rate, and the cost of culture should be reduced for realistically clinical settings. In our study, we aimed to improve the success rate and reduce the cost of establishing advanced prostate cancer organoids from TUR-P specimens. Methods: We optimized and improved both the organoid culture protocol and the fetal bovine serum (FBS) based-organoid culture medium, which is suitable for performing drug testing in a short turnaround time. To confirm that the generated organoids could recapitulate the tumor heterogeneity of original tissues, the organoids were validated with histological, immunohistochemical, and genomic analyses. Results: Following the optimized protocol, we successfully generated organoids in approximately 18 out of 29 cases (or 62.07%), which exhibited effective growth and survival. In addition, we found that the established organoids efficiently identified and captured tumor characteristics present in their matched original tissues, as indicated by histological, immunohistochemical, and comprehensive genomic analysis. As a proof of concept for personalized medicine, the generated organoids were treated with anti-cancer drugs, including docetaxel and enzalutamide in parallel with the clinical treatments. Interestingly, the in vitro drug screening results were positively correlated with the patient outcomes at the clinical level. Conclusions: Taken together, the established APC organoids were able to precisely predict patients’ outcomes for treatment decision-making within a month in a cost-effective manner. Full article
(This article belongs to the Special Issue 3D Cultures and Organoids in Cancer Research)
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Review

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42 pages, 2533 KB  
Review
Epigenetic and Transcriptional Reprogramming in 3D Culture Models in Breast Cancer
by Laura Cecilia Flores-García, Karla Rubio, Eloisa Ibarra-Sierra, Macrina B. Silva-Cázares, Carlos Palma-Flores and César López-Camarillo
Cancers 2025, 17(23), 3830; https://doi.org/10.3390/cancers17233830 - 29 Nov 2025
Cited by 1 | Viewed by 1594
Abstract
Breast cancer remains the leading cause of cancer-related death in women worldwide. This disease is characterized by its molecular and phenotypic heterogeneity, which hinders the development of effective therapies. While two-dimensional (2D) monolayer cell cultures are widely used, they are insufficient to reproduce [...] Read more.
Breast cancer remains the leading cause of cancer-related death in women worldwide. This disease is characterized by its molecular and phenotypic heterogeneity, which hinders the development of effective therapies. While two-dimensional (2D) monolayer cell cultures are widely used, they are insufficient to reproduce the characteristics of the tumor microenvironment, thus limiting our understanding of cancer biology. In this context, three-dimensional (3D) models have emerged as representative tools that more accurately reproduce tissue architecture, cell signaling, and nutrients and oxygen gradients. These cellular models offer greater similarity to primary tissues, improving the study of relevant biological processes. Although 3D cultures provide numerous advantages in cancer research, there is no unified model that standardizes the matrix type and parameters such as gelation time or porosity, hindering the reproducibility and interpretability of the data. This review integrates evidence from various studies to evaluate the effect of epigenetic variations generated by 3D culture methods, which are regulated by mechanotransduction and, consequently, by signaling pathways such as integrin/FAK-ILK/Rho-YAP derived from interactions of cells with extracellular matrix-enriched scaffolds. This affects processes such as DNA methylation, histone coding, and the regulation of non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in different molecular subtypes of breast cancer. Overall, the evidence highlights that 3D culture methods are not equivalent but rather generate distinct epigenetic signatures at the non-coding RNA level that influence the proliferation, differentiation, therapeutic resistance, and metastatic potential of tumor cells. Furthermore, the evidence suggests that histone coding patterns, primarily through the reduction of acetylation marks, are conserved regardless of the type of 3D culture. In summary, the study highlights that the microarchitectural and compositional characteristics of 3D scaffolds are key determinants of epigenetic plasticity. Full article
(This article belongs to the Special Issue 3D Cultures and Organoids in Cancer Research)
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21 pages, 2024 KB  
Review
Spatial Transcriptomics in Lung Cancer and Pulmonary Diseases: A Comprehensive Review
by Da Hyun Kang, Yoonjoo Kim, Ji Hyeon Lee, Hyeong Seok Kang and Chaeuk Chung
Cancers 2025, 17(12), 1912; https://doi.org/10.3390/cancers17121912 - 9 Jun 2025
Cited by 15 | Viewed by 7825
Abstract
Recent advancements in spatial transcriptomics (ST) have revolutionized our understanding of the lung’s cellular organization and pathological alterations. By preserving the spatial distribution of gene expression, ST reveals localized immune niches, stromal–epithelial interactions, and disease-associated transcriptional “hotspots” that cannot be captured by conventional [...] Read more.
Recent advancements in spatial transcriptomics (ST) have revolutionized our understanding of the lung’s cellular organization and pathological alterations. By preserving the spatial distribution of gene expression, ST reveals localized immune niches, stromal–epithelial interactions, and disease-associated transcriptional “hotspots” that cannot be captured by conventional sequencing methods alone. In lung cancer, ST-based investigations have delineated distinct tumor microenvironments between tumor cores and invasive fronts, revealing prognostically significant gene signatures and identifying subpopulations with differential responses to immunotherapy and chemotherapy. Similarly, in chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis, ST has mapped the ecosystem, including immune cells, inflammatory mediators, and fibroblast subtypes, of discrete regions within diseased lung tissue, offering mechanistic insights into disease progression and tissue remodeling. In addition, a more recent ST study provides spatial information for where drugs act within tissues. This review highlights the emerging role of spatial transcriptomics in respiratory research, demonstrating its potential to refine disease classification, elucidate mechanisms of therapeutic resistance, and inform spatially guided personalized interventions in respiratory diseases. Full article
(This article belongs to the Special Issue 3D Cultures and Organoids in Cancer Research)
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