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Cancer Organoids in Basic Science and Translational Medicine

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 67313

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Dr. Flavio Rizzolio

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Department of Molecular Science and Nanosystems, Università Ca' Foscari Venezia, Venice, Italy
Interests: cancer therapy; signaling pathways; precision medicine; drug delivery system
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Prof. Dr. Vincenzo Canzonieri

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Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
Interests: GI; GYN; soft tissue tumors; lymphomas; skin tumors; rare tumors

Dr. Lorenzo Memeo

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Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy
Interests: gastrointestinal tumors; endocrine tumors; urological tumors; breast tumors
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Special Issue Information

Dear Colleagues,

Organoids, a type of cellular 3D microstructure that can expand almost indefinitely under appropriate niche factors, are revolutionizing sample specimen collection. Following the pioneering experiments done by a few laboratories, private and public initiatives are under development for worldwide dissemination of this resource for modelling human pathologies. In the cancer field, it was demonstrated that all phases of cancer progression can be reproduced also from a single patient needle biopsy. Somatic mutations, DNA methylation, transcriptomics, drug response, drug sensitivity, and predictive biomarkers of drug response can be studied under a real, feasible, and economical personalized approach. This Special Issue aims to provide an overview of the last research on the following: (a) initiatives on biobank collection; (b) improved approaches to recreate the cancer microenvironment; (c) biomaterials to mimic the extracellular environment; (d) chip technology to mimic the human body; (e) molecular and cellular approaches to reproduce cancer; and (f) applications in cancer translational medicine.

Dr. Flavio Rizzolio
Prof. Dr. Vincenzo Canzonieri
Dr. Lorenzo Memeo
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 100 words) can be sent to the Editorial Office for announcement on this website.

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.

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Keywords

organoids
tumoroids
living biobanks
tumour microenvironment
biomaterials
organs on chip
diagnosis
therapy

Published Papers (13 papers)

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Editorial

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3 pages, 178 KiB

Open AccessEditorial

Cancer Organoids in Basic Science and Translational Medicine

by Lorenzo Memeo, Vincenzo Canzonieri and Flavio Rizzolio

Cancers 2021, 13(15), 3701; https://doi.org/10.3390/cancers13153701 - 23 Jul 2021

Cited by 3 | Viewed by 1715

Abstract

Organoids are revolutionizing approaches to cancer therapy and even diagnosis [...] Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

Research

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18 pages, 5461 KiB

Open AccessArticle

Breast Cancer Organoids Model Patient-Specific Response to Drug Treatment

by Elena Campaner, Alessandro Zannini, Mariangela Santorsola, Deborah Bonazza, Cristina Bottin, Valeria Cancila, Claudio Tripodo, Marina Bortul, Fabrizio Zanconati, Stefan Schoeftner and Giannino Del Sal

Cancers 2020, 12(12), 3869; https://doi.org/10.3390/cancers12123869 - 21 Dec 2020

Cited by 42 | Viewed by 7008

Abstract

Tumor organoids are tridimensional cell culture systems that are generated in vitro from surgically resected patients’ tumors. They can be propagated in culture maintaining several features of the tumor of origin, including cellular and genetic heterogeneity, thus representing a promising tool for precision cancer medicine. Here, we established patient-derived tumor organoids (PDOs) from different breast cancer subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple negative). The established model systems showed histological and genomic concordance with parental tumors. However, in PDOs, the ratio of diverse cell populations was frequently different from that originally observed in parental tumors. We showed that tumor organoids represent a valuable system to test the efficacy of standard therapeutic treatments and to identify drug resistant populations within tumors. We also report that inhibitors of mechanosignaling and of Yes-associated protein 1 (YAP) activation can restore chemosensitivity in drug resistant tumor organoids. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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15 pages, 3936 KiB

Open AccessArticle

Patient-Derived Papillary Thyroid Cancer Organoids for Radioactive Iodine Refractory Screening

by Luc H.J. Sondorp, Vivian M.L. Ogundipe, Andries H. Groen, Wendy Kelder, Annelies Kemper, Thera P. Links, Robert P. Coppes and Schelto Kruijff

Cancers 2020, 12(11), 3212; https://doi.org/10.3390/cancers12113212 - 31 Oct 2020

Cited by 27 | Viewed by 4076

Abstract

Patients with well-differentiated thyroid cancer, especially papillary thyroid cancer (PTC), are treated with surgical resection of the thyroid gland. This is followed by post-operative radioactive iodine (I¹³¹), resulting in total thyroid ablation. Unfortunately, about 15-33% of PTC patients are unable to take up I¹³¹, limiting further treatment options. The aim of our study was to develop a cancer organoid model with the potential for pre-treatment diagnosis of these I¹³¹-resistant patients. PTC tissue from thirteen patients was used to establish a long-term organoid model. These organoids showed a self-renewal potential for at least five passages, suggesting the presence of cancer stem cells. We demonstrated that thyroid specific markers, a PTC marker, and transporters/receptors necessary for iodine uptake and thyroid hormone production were expressed on a gene and protein level. Additionally, we cultured organoids from I¹³¹-resistant PTC material from three patients. When comparing PTC organoids to radioactive iodine (RAI)-refractory disease (RAIRD) organoids, a substantial discordance on both a protein and gene expression level was observed, indicating a treatment prediction potential. We showed that patient-derived PTC organoids recapitulate PTC tissue and a RAIRD phenotype. Patient-specific PTC organoids may enable the early identification of I¹³¹-resistant patients, in order to reduce RAI overtreatment and its many side effects for thyroid cancer patients. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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23 pages, 4461 KiB

Open AccessArticle

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

by Nicholas R. Hum, Aimy Sebastian, Sean F. Gilmore, Wei He, Kelly A. Martin, Aubree Hinckley, Karen R. Dubbin, Monica L. Moya, Elizabeth K. Wheeler, Matthew A. Coleman and Gabriela G. Loots

Cancers 2020, 12(3), 690; https://doi.org/10.3390/cancers12030690 - 14 Mar 2020

Cited by 14 | Viewed by 5399

Abstract

Current pre-clinical models of cancer fail to recapitulate the cancer cell behavior in primary tumors primarily because of the lack of a deeper understanding of the effects that the microenvironment has on cancer cell phenotype. Transcriptomic profiling of 4T1 murine mammary carcinoma cells from 2D and 3D cultures, subcutaneous or orthotopic allografts (from immunocompetent or immunodeficient mice), as well as ex vivo tumoroids, revealed differences in molecular signatures including altered expression of genes involved in cell cycle progression, cell signaling and extracellular matrix remodeling. The 3D culture platforms had more in vivo-like transcriptional profiles than 2D cultures. In vivo tumors had more cells undergoing epithelial-to-mesenchymal transition (EMT) while in vitro cultures had cells residing primarily in an epithelial or mesenchymal state. Ex vivo tumoroids incorporated aspects of in vivo and in vitro culturing, retaining higher abundance of cells undergoing EMT while shifting cancer cell fate towards a more mesenchymal state. Cellular heterogeneity surveyed by scRNA-seq revealed that ex vivo tumoroids, while rapidly expanding cancer and fibroblast populations, lose a significant proportion of immune components. This study emphasizes the need to improve in vitro culture systems and preserve syngeneic-like tumor composition by maintaining similar EMT heterogeneity as well as inclusion of stromal subpopulations. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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18 pages, 3328 KiB

Open AccessArticle

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

by Francesca Sensi, Edoardo D’Angelo, Martina Piccoli, Piero Pavan, Francesca Mastrotto, Paolo Caliceti, Andrea Biccari, Diana Corallo, Luca Urbani, Matteo Fassan, Gaya Spolverato, Pietro Riello, Salvatore Pucciarelli and Marco Agostini

Cancers 2020, 12(3), 681; https://doi.org/10.3390/cancers12030681 - 13 Mar 2020

Cited by 33 | Viewed by 4601

Abstract

Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient’s disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC₅₀) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC₅₀ fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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11 pages, 2105 KiB

Open AccessArticle

In Vitro Characterization of Cisplatin and Pemetrexed Effects in Malignant Pleural Mesothelioma 3D Culture Phenotypes

by Eleftherios D. Papazoglou, Rajesh M. Jagirdar, Olympia A. Kouliou, Eleanna Pitaraki, Chrissi Hatzoglou, Konstantinos I. Gourgoulianis and Sotirios G. Zarogiannis

Cancers 2019, 11(10), 1446; https://doi.org/10.3390/cancers11101446 - 27 Sep 2019

Cited by 11 | Viewed by 3035

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. The main treatment for MPM is doublet chemotherapy with Cisplatin and Pemetrexed, while ongoing trials test the efficacy of pemetrexed monotherapy. However, there is lack of evidence regarding the effects of Cisplatin and Pemetrexed on MPM cell phenotypes, especially in three-dimensional (3D) cell cultures. In this study, we evaluated the effects Cisplatin and Pemetrexed on cell viability using homologous cell derived extracellular matrix (hECM) as substratum and subsequently in the following 3D cell culture phenotypes: tumor spheroid formation, tumor spheroid invasion, and collagen gel contraction. We used benign mesothelial MeT-5A cells as controls and the MPM cell lines M14K (epithelioid), MSTO (biphasic), and ZL34 (sarcomatoid). Cell viability of all cell lines was significantly decreased with all treatments. Mean tumor spheroid perimeter was reduced after treatment with Pemetrexed or the doublet therapy in all cell lines, while Cisplatin reduced the mean spheroid perimeter of MeT-5A and MSTO cells. Doublet treatment reduced the invasive capacity of spheroids of cell lines into collagenous matrices, while Cisplatin lowered the invasion of the MSTO and ZL34 cell lines, and Pemetrexed lowered the invasion of MeT-5A and ZL34 cell lines. Treatment with Pemetrexed or the combination significantly reduced the collagen gel contraction of all cell lines, while Cisplatin treatment affected only the MeT-5A and M14K cells. The results of the current study can be used as an in vitro 3D platform for testing novel drugs against MPM for ameliorating the effects of first line chemotherapeutics. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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Review

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34 pages, 15361 KiB

Open AccessEditor’s ChoiceReview

Microfluidic Organoids-on-a-Chip: Quantum Leap in Cancer Research

by Fahriye Duzagac, Gloria Saorin, Lorenzo Memeo, Vincenzo Canzonieri and Flavio Rizzolio

Cancers 2021, 13(4), 737; https://doi.org/10.3390/cancers13040737 - 10 Feb 2021

Cited by 51 | Viewed by 8382

Abstract

Organ-like cell clusters, so-called organoids, which exhibit self-organized and similar organ functionality as the tissue of origin, have provided a whole new level of bioinspiration for ex vivo systems. Microfluidic organoid or organs-on-a-chip platforms are a new group of micro-engineered promising models that recapitulate 3D tissue structure and physiology and combines several advantages of current in vivo and in vitro models. Microfluidics technology is used in numerous applications since it allows us to control and manipulate fluid flows with a high degree of accuracy. This system is an emerging tool for understanding disease development and progression, especially for personalized therapeutic strategies for cancer treatment, which provide well-grounded, cost-effective, powerful, fast, and reproducible results. In this review, we highlight how the organoid-on-a-chip models have improved the potential of efficiency and reproducibility of organoid cultures. More widely, we discuss current challenges and development on organoid culture systems together with microfluidic approaches and their limitations. Finally, we describe the recent progress and potential utilization in the organs-on-a-chip practice. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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22 pages, 1568 KiB

Open AccessReview

Patient-Derived Tumor Organoids for Drug Repositioning in Cancer Care: A Promising Approach in the Era of Tailored Treatment

by Silvia Vivarelli, Saverio Candido, Giuseppe Caruso, Luca Falzone and Massimo Libra

Cancers 2020, 12(12), 3636; https://doi.org/10.3390/cancers12123636 - 4 Dec 2020

Cited by 25 | Viewed by 3974

Abstract

Malignancies heterogeneity represents a critical issue in cancer care, as it often causes therapy resistance and tumor relapse. Organoids are three-dimensional (3D) miniaturized representations of selected tissues within a dish. Lately, organoid technology has been applied to oncology with growing success and Patients Derived Tumor Organoids (PDTOs) constitute a novel available tool which fastens cancer research. PDTOs are in vitro models of cancer, and importantly, they can be used as a platform to validate the efficacy of anti-cancer drugs. For that reason, they are currently utilized in clinics as emerging in vitro screening technology to tailor the therapy around the patient, with the final goal of beating cancer resistance and recurrence. In this sense, PDTOs biobanking is widely used and PDTO-libraries are helping the discovery of novel anticancer molecules. Moreover, they represent a good model to screen and validate compounds employed for other pathologies as off-label drugs potentially repurposed for the treatment of tumors. This will open up novel avenues of care thus ameliorating the life expectancy of cancer patients. This review discusses the present advancements in organoids research applied to oncology, with special attention to PDTOs and their translational potential, especially for anti-cancer drug testing, including off-label molecules. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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16 pages, 770 KiB

Open AccessReview

The Organoid Era Permits the Development of New Applications to Study Glioblastoma

by Francesco Andreatta, Giulia Beccaceci, Nicolò Fortuna, Martina Celotti, Dario De Felice, Marco Lorenzoni, Veronica Foletto, Sacha Genovesi, Josep Rubert and Alessandro Alaimo

Cancers 2020, 12(11), 3303; https://doi.org/10.3390/cancers12113303 - 9 Nov 2020

Cited by 22 | Viewed by 4091

Abstract

Glioblastoma (GB) is the most frequent and aggressive type of glioma. The lack of reliable GB models, together with its considerable clinical heterogeneity, has impaired a comprehensive investigation of the mechanisms that lead to tumorigenesis, cancer progression, and response to treatments. Recently, 3D cultures have opened the possibility to overcome these challenges and cerebral organoids are emerging as a leading-edge tool in GB research. The opportunity to easily engineer brain organoids via gene editing and to perform co-cultures with patient-derived tumor spheroids has enabled the analysis of cancer development in a context that better mimics brain tissue architecture. Moreover, the establishment of biobanks from GB patient-derived organoids represents a crucial starting point to improve precision medicine therapies. This review exemplifies relevant aspects of 3D models of glioblastoma, with a specific focus on organoids and their involvement in basic and translational research. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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18 pages, 1958 KiB

Open AccessReview

Pancreatic Ductal Adenocarcinoma (PDAC) Organoids: The Shining Light at the End of the Tunnel for Drug Response Prediction and Personalized Medicine

by Pierre-Olivier Frappart and Thomas G. Hofmann

Cancers 2020, 12(10), 2750; https://doi.org/10.3390/cancers12102750 - 24 Sep 2020

Cited by 32 | Viewed by 6118

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic malignancies. In contrast to many other tumor entities, the prognosis of PDAC has not significantly improved during the past thirty years. Patients are often diagnosed too late, leading to an overall five-year survival rate below 10%. More dramatically, PDAC cases are on the rise and it is expected to become the second leading cause of death by cancer in western countries by 2030. Currently, the use of gemcitabine/nab-paclitaxel or FOLFIRINOX remains the standard chemotherapy treatment but still with limited efficiency. There is an urgent need for the development of early diagnostic and therapeutic tools. To this point, in the past 5 years, organoid technology has emerged as a revolution in the field of PDAC personalized medicine. Here, we are reviewing and discussing the current technical and scientific knowledge on PDAC organoids, their future perspectives, and how they can represent a game change in the fight against PDAC by improving both diagnosis and treatment options. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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19 pages, 685 KiB

Open AccessReview

Promising Applications of Tumor Spheroids and Organoids for Personalized Medicine

by Zarema Gilazieva, Aleksei Ponomarev, Catrin Rutland, Albert Rizvanov and Valeriya Solovyeva

Cancers 2020, 12(10), 2727; https://doi.org/10.3390/cancers12102727 - 23 Sep 2020

Cited by 74 | Viewed by 8528

Abstract

One of the promising directions in personalized medicine is the use of three-dimensional (3D) tumor models such as spheroids and organoids. Spheroids and organoids are three-dimensional cultures of tumor cells that can be obtained from patient tissue and, using high-throughput personalized medicine methods, provide a suitable therapy for that patient. These 3D models can be obtained from most types of tumors, which provides opportunities for the creation of biobanks with appropriate patient materials that can be used to screen drugs and facilitate the development of therapeutic agents. It should be noted that the use of spheroids and organoids would expand the understanding of tumor biology and its microenvironment, help develop new in vitro platforms for drug testing and create new therapeutic strategies. In this review, we discuss 3D tumor spheroid and organoid models, their advantages and disadvantages, and evaluate their promising use in personalized medicine. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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12 pages, 4308 KiB

Open AccessReview

An Organotypic Microcosm for the Pancreatic Tumor Microenvironment

by Miranda Lin, Mei Gao, Prakash K. Pandalai, Michael J. Cavnar and Joseph Kim

Cancers 2020, 12(4), 811; https://doi.org/10.3390/cancers12040811 - 28 Mar 2020

Cited by 7 | Viewed by 3715

Abstract

Pancreatic duct adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths in the next few years. Unfortunately, the development of novel therapies for PDAC has been challenged by a uniquely complex tumor microenvironment. The development of in vitro cancer organoids in recent years has demonstrated potential to increase therapies for patients with PDAC. Organoids have been established from PDAC murine and human tissues and they are representative of the primary tumor. Further, organoids have been shown beneficial in studies of molecular mechanisms and drug sensitivity testing. This review will cover the use of organoids to study PDAC development, invasiveness, and therapeutic resistance in the context of the tumor microenvironment, which is characterized by a dense desmoplastic reaction, hindered immune activity, and pro-tumor metabolic signaling. We describe investigations utilizing organoids to characterize the tumor microenvironment and also describe their limitations. Overall, organoids have great potential to serve as a versatile model of drug response and may be used to increase available therapies and improve survival for patients with PDAC. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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18 pages, 2400 KiB

Open AccessFeature PaperReview

Development of Prostate Cancer Organoid Culture Models in Basic Medicine and Translational Research

by Mohamed Elbadawy, Amira Abugomaa, Hideyuki Yamawaki, Tatsuya Usui and Kazuaki Sasaki

Cancers 2020, 12(4), 777; https://doi.org/10.3390/cancers12040777 - 25 Mar 2020

Cited by 36 | Viewed by 5396

Abstract

Prostate cancer (PC) is the most prevalent cancer in men and the second main cause of cancer-related death in Western society. The lack of proper PC models that recapitulate the molecular and genomic landscape of clinical disease has hampered progress toward translational research to understand the disease initiation, progression, and therapeutic responses in each patient. Although several models have been developed, they hardly emulated the complicated PC microenvironment. Precision medicine is an emerging approach predicting appropriate therapies for individual cancer patients by means of various analyses of individual genomic profiling and targeting specific cancer pathways. In PC, precision medicine also has the potential to impose changes in clinical practices. Here, we describe the various PC models with special focus on PC organoids and their values in basic medicine, personalized therapy, and translational researches in vitro and in vivo, which could help to achieve the full transformative power of cancer precision medicine. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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