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Tumor Organoids Uncovered: A Molecular Lens on Cancer Complexity
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Tumor Organoids Uncovered: A Molecular Lens on Cancer Complexity

A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 May 2026) | Viewed by 4115

Editors

Dr. Eleftherios Makris

E-Mail Website
Guest Editor
Department of Surgery, Division of Surgical Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
Interests: oncology; patient-derived organoids (PDOs); mutational profiling; tumor-reactive lymphocytes
Prof. Dr. Konstantinos Ioannis Votanopoulos

E-Mail Website
Guest Editor
Wake Forest School of Medicine, Wake Forest University, Winston Salem, NC 27101, USA
Interests: tumor organoid technology; pseudomyxoma peritonei; cytoreductive surgery; peritoneum tumor
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to our upcoming Special Issue titled "Tumor Organoids Uncovered: A Molecular Lens on Cancer Complexity."

Tumor organoids have emerged as revolutionary three-dimensional culture systems that recapitulate the complex architecture, cellular heterogeneity, and molecular characteristics of human cancers. These sophisticated in vitro models bridge the gap between traditional two-dimensional cell cultures and animal models, offering unprecedented opportunities to study cancer biology, drug resistance mechanisms, and personalized therapeutic approaches. The field has rapidly evolved from basic research applications to clinical translation, with organoids now being used for precision medicine, drug screening, and biomarker discovery. The molecular complexity captured by these systems provides insights into tumor microenvironment interactions, metabolic reprogramming, and therapeutic vulnerabilities that were previously inaccessible.

This Special Issue aims to showcase cutting-edge translational applications of tumor organoid technology, emphasizing their role in advancing our molecular understanding of cancer complexity and their clinical implementation. The scope aligns with IJMS's focus on molecular sciences by highlighting the molecular mechanisms underlying organoid biology, their applications in precision oncology, and their potential for therapeutic innovation. We seek to present comprehensive insights into how organoid models are transforming cancer research and clinical practice, from fundamental molecular discoveries to patient-derived applications.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Patient-derived organoid models for precision medicine and therapeutic stratification;
  • Molecular characterization and genomic profiling of tumor organoids;
  • Drug screening and resistance mechanisms using organoid platforms;
  • Organoid-based biomarker discovery and validation;
  • Tumor microenvironment modeling in organoid systems;
  • Single-cell and multi-omics approaches in organoid research;
  • Organoid co-culture systems and immune cell interactions;
  • Clinical translation and regulatory considerations for organoid-based assays;
  • Artificial intelligence and machine learning applications in organoid analysis;
  • Organoid biobanking and standardization protocols;
  • Therapeutic target identification using organoid models;
  • Organoid applications in rare cancer research.

We look forward to receiving your contributions.

Dr. Eleftherios Makris
Prof. Dr. Konstantinos Ioannis Votanopoulos
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 short 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • tumor organoids
  • precision medicine
  • cancer modeling
  • drug screening
  • patient-derived models
  • molecular characterization
  • personalized therapy
  • translational research
  • biomarker discovery
  • clinical application

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Published Papers (3 papers)

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Research

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14 pages, 8787 KB  
Article
Bioprinted Bladder Cancer Organoids Model System for Prediction of Chemotherapy Response and Drug Screening
by Randall G. Bissette, Zachary Congress, Gemma Nomdedeu-Sancho, Nadeem Wajih, Krishnaiah Maddeboina and Shay Soker
Int. J. Mol. Sci. 2026, 27(13), 6082; https://doi.org/10.3390/ijms27136082 - 7 Jul 2026
Viewed by 961
Abstract
Bladder cancer is the fifth most common cancer in the United States, causing approximately 17,000 deaths annually. Due to its vast genetic and molecular heterogeneity, presentation, prognosis, and therapeutic response vary greatly between individuals. To improve patient outcomes, there is a need for [...] Read more.
Bladder cancer is the fifth most common cancer in the United States, causing approximately 17,000 deaths annually. Due to its vast genetic and molecular heterogeneity, presentation, prognosis, and therapeutic response vary greatly between individuals. To improve patient outcomes, there is a need for better drug-screening platforms. The genetic heterogeneity of bladder cancer often leads to chemotherapy resistance or low response rates. Moreover, chemotherapies are often contraindicated in patients with select comorbidities. Organoids offer a better option to replicate the tumor microenvironment than traditional 2D cell cultures, improving drug development and personalized therapy. In this study, we bioprinted gelatin-methacrylol (GelMA)-based organoids containing bladder cancer cell lines of different grades to model muscle-invasive bladder cancer. In the organoids, we observed distinct grade-dependent tumor proliferation and progression dynamics. Treatment with standard-of-care chemotherapies revealed a grade-dependent tumor response consistent with in vivo patient data, highlighting the suitability of these organoids for rapid, reliable drug testing. Lastly, we used the organoids to test LCI139, a novel small-molecule inhibitor of PI3K, CDK4/6, and CDK9 designed for the treatment of epithelial cancers, underscoring the potential of our model to evaluate the efficacy of newly developed drugs. The ability to quickly biofabricate reproducible bladder cancer organoids that are adaptable to different tumor grades represents a novel strategy to create an in vitro platform with strong potential to predict treatment outcomes of bladder cancer patients. Full article
(This article belongs to the Special Issue Tumor Organoids Uncovered: A Molecular Lens on Cancer Complexity)
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19 pages, 7615 KB  
Article
A Rapid 3D Melanoma–Skin Organoid for High-Throughput Assessment of Tumor Dynamics and Drug Response
by Gemma Nomdedeu-Sancho, Nicholas Edenhoffer, Anastasiya Gorkun-Roeder, Ola A. Gaser, Carlos Kengla, Allie Benton, David W. Mullins, Anthony Atala and Shay Soker
Int. J. Mol. Sci. 2026, 27(12), 5314; https://doi.org/10.3390/ijms27125314 - 12 Jun 2026
Viewed by 1227
Abstract
Melanoma is the most aggressive type of skin cancer, driven by early invasion, phenotypic plasticity, and frequent resistance to targeted therapies. Although genomic profiling informs treatment selection, genotype alone often fails to predict therapeutic response, underscoring the need for rapid and physiologically relevant [...] Read more.
Melanoma is the most aggressive type of skin cancer, driven by early invasion, phenotypic plasticity, and frequent resistance to targeted therapies. Although genomic profiling informs treatment selection, genotype alone often fails to predict therapeutic response, underscoring the need for rapid and physiologically relevant functional testing platforms. Here, we present a three-dimensional melanoma–skin organoid (mSO) model that integrates primary skin cells with melanoma cell lines in a self-assembling, high-throughput format. The spherical mSOs recapitulate native human skin architecture, including a stratified epidermis and a dermal–hypodermal core, while supporting melanoma growth within an appropriate tissue microenvironment. In this niche, melanoma cells display epidermal spreading in radial growth-like patterns, outward invasion, and transcriptional shifts toward a pro-invasive phenotype. Using live confocal imaging coupled with a custom automated image analysis pipeline, we quantitatively measured tumor growth, migration beyond the organoid boundary, and interactions between melanoma cells and normal melanocytes. The mSOs also captured genotype-specific drug responses: BRAF-mutant melanoma cells were sensitive to BRAF and MEK inhibition, whereas NRAS-mutant, BRAF–wild-type cells were resistant to BRAF inhibition but remained responsive to MEK inhibition. Altogether, our mSO platform combines architectural and functional complexity with experimental scalability, providing a robust framework for modeling melanoma progression and evaluating targeted therapeutic responses within a relevant skin microenvironment. In the future, adaptation of this system to include patient-derived tumor cells could support personalized therapeutic decision-making in melanoma. Full article
(This article belongs to the Special Issue Tumor Organoids Uncovered: A Molecular Lens on Cancer Complexity)
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Review

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17 pages, 1989 KB  
Review
Patient-Derived Organoid Models and Precision HIPEC in Diffuse Malignant Peritoneal Mesothelioma: Modeling Heterogeneity to Address Recurrence
by Eleftherios A. Makris, James K. Ives and Konstantinos Votanopoulos
Int. J. Mol. Sci. 2026, 27(17), 7911; https://doi.org/10.3390/ijms27177911 - 4 Sep 2026
Viewed by 349
Abstract
Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy for which cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is central to treatment in appropriately selected patients. Recurrence remains common even after complete macroscopic cytoreduction. Current HIPEC regimens are protocolized at the institutional [...] Read more.
Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy for which cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is central to treatment in appropriately selected patients. Recurrence remains common even after complete macroscopic cytoreduction. Current HIPEC regimens are protocolized at the institutional and population levels but are not individualized using site-specific molecular or functional tumor biology. We performed a narrative review of clinical, genomic, epigenetic, immune, microenvironmental, and patient-derived organoid evidence relevant to DMPM, CRS/HIPEC, and treatment resistance. Recurrence is multifactorial, with plausible contributions from spatial, histologic, genomic, epigenetic, immune, stromal, and pharmacokinetic heterogeneity. Three primary reports provide direct DMPM organoid evidence, including preliminary demonstrations of patient-specific drug response and discordant responses among anatomically distinct implants. However, these platforms differ biologically, and predictive thresholds, analytical reproducibility, turnaround time, and microenvironmental modeling remain unvalidated. Multi-site organoid pharmacotyping integrated with molecular profiling is therefore a plausible strategy for studying HIPEC resistance. Translation requires a staged pathway encompassing analytical validity, blinded clinical validity, and clinical-utility testing. Precision HIPEC should presently be considered an investigational, validation-ready framework rather than a standard of care. Full article
(This article belongs to the Special Issue Tumor Organoids Uncovered: A Molecular Lens on Cancer Complexity)
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