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1
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Wimmers DG, Huebner K, Dale T, Papargyriou A, Reichert M, Hartmann A, Schneider-Stock R. A floating collagen matrix triggers ring formation and stemness characteristics in human colorectal cancer organoids. Pathol Res Pract 2025; 269:155890. [PMID: 40073643 DOI: 10.1016/j.prp.2025.155890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 02/06/2025] [Accepted: 03/01/2025] [Indexed: 03/14/2025]
Abstract
Intestinal organoids reflect the 3D structure and function of their original tissues. Organoid are typically cultured in Matrigel, an extracellular matrix (ECM) mimicking the basement membrane, which is suitable for epithelial cells but does not accurately mimic the tumour microenvironment of colorectal cancer (CRC). The ECM and particularly collagen type I is crucial for CRC progression and invasiveness. Given that efforts to examine CRC organoid invasion in a more physiologically relevant ECM have been limited, we used a floating collagen type I matrix (FC) to study organoid invasion in three patient-derived CRC organoid lines. In FC gel, organoids contract, align, and fuse into macroscopic ring structures, initiating minor branch formation and invasion fronts, phenomena unique for the collagen ECM and otherwise not observed in Matrigel-grown CRC organoids. In contrast to Matrigel, FC organoids showed basal extrusion with improper actin localization, but without change in the organoid polarity. Moreover, small clusters of vital invading cells were observed. Gene expression analysis revealed that the organoids cultured in a FC matrix presented more epithelial and stem cell-like characteristics. This novel technique of cultivating CRC organoids in a FC matrix represents an in-vitro model for studying cancer organization and matrix remodelling with increased organoid stemness potential.
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Affiliation(s)
- Daniel Gerhard Wimmers
- Experimental Tumorpathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany; Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Kerstin Huebner
- Experimental Tumorpathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany; Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Trevor Dale
- Cardiff University, European Cancer Stem Cell Research Institute (ECSCRI), School of Bioscience, Cardiff, United Kingdom
| | - Aristeidis Papargyriou
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Technical University of Munich, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Munich, Germany; Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, 85764, Germany
| | - Maximilian Reichert
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Technical University of Munich, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Munich, Germany; Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, 85764, Germany; Center for Organoid Systems, Technical University of Munich, Garching, Germany; Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich, Garching, Germany; German Center for Translational Cancer Research (DKTK), Munich, Germany; Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Arndt Hartmann
- Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Regine Schneider-Stock
- Experimental Tumorpathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany; Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Bavarian Cancer Research Center (BZKF), Erlangen, Germany.
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2
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Xu Q, Halle L, Hediyeh-Zadeh S, Kuijs M, Riedweg R, Kilik U, Recaldin T, Yu Q, Rall I, Frum T, Adam L, Parikh S, Kfuri-Rubens R, Gander M, Klein D, Curion F, He Z, Fleck JS, Oost K, Kahnwald M, Barbiero S, Mitrofanova O, Maciag GJ, Jensen KB, Lutolf M, Liberali P, Spence JR, Gjorevski N, Beumer J, Treutlein B, Theis FJ, Camp JG. An integrated transcriptomic cell atlas of human endoderm-derived organoids. Nat Genet 2025; 57:1201-1212. [PMID: 40355592 DOI: 10.1038/s41588-025-02182-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/27/2025] [Indexed: 05/14/2025]
Abstract
Human pluripotent stem cells and tissue-resident fetal and adult stem cells can generate epithelial tissues of endodermal origin in vitro that recapitulate aspects of developing and adult human physiology. Here, we integrate single-cell transcriptomes from 218 samples covering organoids and other models of diverse endoderm-derived tissues to establish an initial version of a human endoderm-derived organoid cell atlas. The integration includes nearly one million cells across diverse conditions, data sources and protocols. We compare cell types and states between organoid models and harmonize cell annotations through mapping to primary tissue counterparts. Focusing on the intestine and lung, we provide examples of mapping data from new protocols and show how the atlas can be used as a diverse cohort to assess perturbations and disease models. The human endoderm-derived organoid cell atlas makes diverse datasets centrally available and will be valuable to assess fidelity, characterize perturbed and diseased states, and streamline protocol development.
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Affiliation(s)
- Quan Xu
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.
| | - Lennard Halle
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
| | - Soroor Hediyeh-Zadeh
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- School of Life Sciences, Technical University of Munich, Munich, Germany
| | - Merel Kuijs
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
| | - Rya Riedweg
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Umut Kilik
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
- Biozentrum, University of Basel, Basel, Switzerland
| | - Timothy Recaldin
- Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland
| | - Qianhui Yu
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Isabell Rall
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Tristan Frum
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Lukas Adam
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Shrey Parikh
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- School of Life Sciences, Technical University of Munich, Munich, Germany
| | - Raphael Kfuri-Rubens
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- IIIrd Medical Department, Klinikum rechts der Isar, Munich, Germany
- School of Medicine, Technical University of Munich, Munich, Germany
| | - Manuel Gander
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
| | - Dominik Klein
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
| | - Fabiola Curion
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany
- School of Computation, Information and Technology, Technical University of Munich, Munich, Germany
| | - Zhisong He
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
| | - Jonas Simon Fleck
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Koen Oost
- Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland
| | - Maurice Kahnwald
- Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland
| | - Silvia Barbiero
- Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland
| | - Olga Mitrofanova
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Grzegorz Jerzy Maciag
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, University of Copenhagen, Copenhagen, Denmark
| | - Kim B Jensen
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, University of Copenhagen, Copenhagen, Denmark
| | - Matthias Lutolf
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
- Laboratory of Stem Cell Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Prisca Liberali
- Biozentrum, University of Basel, Basel, Switzerland
- Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland
| | - Jason R Spence
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
| | - Nikolche Gjorevski
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Joep Beumer
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Barbara Treutlein
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
| | - Fabian J Theis
- Department of Computational Health, Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany.
- School of Life Sciences, Technical University of Munich, Munich, Germany.
- School of Computation, Information and Technology, Technical University of Munich, Munich, Germany.
| | - J Gray Camp
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.
- Biozentrum, University of Basel, Basel, Switzerland.
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Hanitrarimalala V, Prgomet Z, Hedhammar M, Tassidis H, Wingren AG. In vitro 3D modeling of colorectal cancer: the pivotal role of the extracellular matrix, stroma and immune modulation. Front Genet 2025; 16:1545017. [PMID: 40376304 PMCID: PMC12078225 DOI: 10.3389/fgene.2025.1545017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/23/2025] [Indexed: 05/18/2025] Open
Abstract
Colorectal cancer (CRC) is a leading global cancer with high mortality, especially in metastatic cases, with limited therapeutic options. The tumor microenvironment (TME), a network comprising various immune cells, stromal cells and extracellular (ECM) components plays a crucial role in influencing tumor progression and therapy outcome. The genetic heterogeneity of CRC and the complex TME complicates the development of effective, personalized treatment strategies. The prognosis has slowly improved during the past decades, but metastatic CRC (mCRC) is common among patients and is still associated with low survival. The therapeutic options for CRC differ from those for mCRC and include surgery (mostly for CRC), chemotherapy, growth factor receptor signaling pathway targeting, as well as immunotherapy. Malignant CRC cells are established in the TME, which varies depending on the primary or metastatic site. Herein, we review the role and interactions of several ECM components in 3D models of CRC and mCRC tumor cells, with an emphasis on how the TME affects tumor growth and treatment. This comprehensive summary provides support for the development of 3D models that mimic the interactions within the TME, which will be essential for the development of novel anticancer therapies.
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Affiliation(s)
- Veroniaina Hanitrarimalala
- Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden
- Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden
| | - Zdenka Prgomet
- Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden
- Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden
| | - My Hedhammar
- KTH Royal Institute of Technology, Division of Protein Technology, Stockholm, Sweden
| | - Helena Tassidis
- Department of Bioanalysis, Faculty of Natural Sciences, Kristianstad University, Kristianstad, Sweden
| | - Anette Gjörloff Wingren
- Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden
- Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden
- Department of Bioanalysis, Faculty of Natural Sciences, Kristianstad University, Kristianstad, Sweden
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Kim SY, van de Wetering M, Clevers H, Sanders K. The future of tumor organoids in precision therapy. Trends Cancer 2025:S2405-8033(25)00073-1. [PMID: 40185656 DOI: 10.1016/j.trecan.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 04/07/2025]
Abstract
Tumoroids are cultures of patient-derived tumor cells, which are grown in 3D in the presence of an extracellular matrix extract and specific growth factors. Tumoroids can be generated from adult as well as pediatric cancers, including epithelial cancers, sarcomas, and brain cancers. Tumoroids retain multi-omic characteristics of their corresponding tumor and recapitulate interpatient and intratumor heterogeneity. Retrospective and prospective studies have demonstrated that tumoroids predict patient responses to anticancer therapies, making them a promising tool for precision oncology. However, several challenges remain before tumoroids can be fully integrated into clinical decision-making, including success rates of tumoroid establishment and turnaround times. This review discusses the current advances, challenges, and future directions of tumoroid-based models in cancer research and precision therapy.
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Affiliation(s)
- Seok-Young Kim
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | | | - Hans Clevers
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, The Netherlands; Current address: Roche Pharmaceutical Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel, Switzerland.
| | - Karin Sanders
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
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Kim B, Park J, Na HY, Park S, Jin J, Jung K, Lee JC, Hwang JH, Seo M, Kim J. The origin of patient-derived cancer organoids from pathologically undiagnosed specimen in patients with pancreatobiliary cancers. Cell Oncol (Dordr) 2025; 48:523-535. [PMID: 39688793 PMCID: PMC11996933 DOI: 10.1007/s13402-024-01026-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
PURPOSE Tissue confirmation of pancreatobiliary cancer is often difficult because of the location of the tumor and structure of the surrounding blood vessels. Patient-derived cancer organoids (PDCOs) reflect the genomic characteristics of individual cancers. Although diverse attempts to construct PDCOs for various pancreatobiliary cancer models are ongoing, no research results have yet confirmed the possibility of performing a precise diagnosis on PDCOs derived from pathologically negative patient samples. METHODS We obtained a total of nine samples, including pathologically negative samples, from four patients (three patients with pancreatic cancer and one patient with gallbladder cancer) using different tissue acquisition methods to establish PDCOs (success rate 75%). RESULTS We successfully verified whether the constructed PDCOs could represent the tissues of patients with pancreatobiliary cancer at each multi-omics level using tumor panel sequencing, single-cell RNA sequencing, hematoxylin and eosin, and immunohistochemical staining. PDCOs from pathologically negative samples showed expression patterns of malignant ductal cell-related biomarkers similar to those of other pathologically positive samples. Furthermore, the expression patterns at the single-cell level in PDCO from patients ultimately diagnosed with gallbladder cancer after surgery were different from those in patients with pancreatic cancer. CONCLUSION Therefore, our study implicated the potential of PDCOs as diagnostic and research tools, including for case involving limited tissue samples. Based on these results, we anticipate that this could be extended to more advanced studies, such as drug sensitivity testing, through large-scale trials in the near future.
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Affiliation(s)
- Bomi Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | | | - Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Sinwoo Park
- Department of Computer and Information Science, Korea University, Sejong, Korea
| | | | - Kwangrok Jung
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Jong-Chan Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Jin-Hyeok Hwang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Minseok Seo
- Department of Computer and Information Science, Korea University, Sejong, Korea.
| | - Jaihwan Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
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Yang Q, Li M, Xiao Z, Feng Y, Lei L, Li S. A New Perspective on Precision Medicine: The Power of Digital Organoids. Biomater Res 2025; 29:0171. [PMID: 40129676 PMCID: PMC11931648 DOI: 10.34133/bmr.0171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/21/2025] [Accepted: 03/04/2025] [Indexed: 03/26/2025] Open
Abstract
Precision medicine is a personalized medical model based on the individual's genome, phenotype, and lifestyle that provides tailored treatment plans for patients. In this context, tumor organoids, a 3-dimensional preclinical model based on patient-derived tumor cell self-organization, combined with digital analysis methods, such as high-throughput sequencing and image processing technology, can be used to analyze the genome, transcriptome, and cellular heterogeneity of tumors, so as to accurately track and assess the growth process, genetic characteristics, and drug responsiveness of tumor organoids, thereby facilitating the implementation of precision medicine. This interdisciplinary approach is expected to promote the innovation of cancer diagnosis and enhance personalized treatment. In this review, the characteristics and culture methods of tumor organoids are summarized, and the application of multi-omics, such as bioinformatics and artificial intelligence, and the digital methods of organoids in precision medicine research are discussed. Finally, this review explores the main causes and potential solutions for the bottleneck in the clinical translation of digital tumor organoids, proposes the prospects of multidisciplinary cooperation and clinical transformation to narrow the gap between laboratory and clinical settings, and provides references for research and development in this field.
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Affiliation(s)
- Qian Yang
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital,
Central South University, Changsha 410011, Hunan, China
| | - Mengmeng Li
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital,
Central South University, Changsha 410011, Hunan, China
| | - Zian Xiao
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital,
Central South University, Changsha 410011, Hunan, China
| | - Yekai Feng
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital,
Central South University, Changsha 410011, Hunan, China
| | - Lanjie Lei
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine,
Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China
| | - Shisheng Li
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital,
Central South University, Changsha 410011, Hunan, China
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Taglieri M, Di Gregorio L, Matis S, Uras CRM, Ardy M, Casati S, Marchese M, Poggi A, Raffaghello L, Benelli R. Colorectal Organoids: Models, Imaging, Omics, Therapy, Immunology, and Ethics. Cells 2025; 14:457. [PMID: 40136707 PMCID: PMC11941511 DOI: 10.3390/cells14060457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/06/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025] Open
Abstract
Colorectal epithelium was the first long-term 3D organoid culture established in vitro. Identification of the key components essential for the long-term survival of the stem cell niche allowed an indefinite propagation of these cultures and the modulation of their differentiation into various lineages of mature intestinal epithelial cells. While these methods were eventually adapted to establish organoids from different organs, colorectal organoids remain a pioneering model for the development of new applications in health and disease. Several basic and applicative aspects of organoid culture, modeling, monitoring and testing are analyzed in this review. We also tackle the ethical problems of biobanking and distribution of these precious research tools, frequently confined in the laboratory of origin or condemned to destruction at the end of the project.
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Affiliation(s)
- Martina Taglieri
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Linda Di Gregorio
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Serena Matis
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Chiara Rosa Maria Uras
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Massimo Ardy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Sara Casati
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” CNR, 80131 Naples, Italy;
- Common Service ELSI, BBMRI.it (UNIMIB National Node Headquarter), 20126 Milan, Italy
| | - Monica Marchese
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Alessandro Poggi
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Lizzia Raffaghello
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
| | - Roberto Benelli
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (M.T.); (L.D.G.); (S.M.); (C.R.M.U.); (M.A.); (M.M.); (A.P.); (L.R.)
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8
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Wawrzak-Pienkowska K, Pienkowski T, Tankiewicz-Kwedlo A, Ciborowski M, Kurek K, Pawlak D. Differences in treatment outcome between translational platforms in developing therapies for gastrointestinal cancers. Eur J Pharmacol 2025; 991:177309. [PMID: 39870234 DOI: 10.1016/j.ejphar.2025.177309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/11/2025] [Accepted: 01/23/2025] [Indexed: 01/29/2025]
Abstract
The variability in translational models profoundly impacts the outcomes and predictive value of preclinical studies for gastrointestinal (GI) cancer treatments. Preclinical models, including 2D cell cultures, 3D organoids, patient-derived xenografts (PDXs), and animal models, provide distinct advantages and limitations in replicating the complex tumor microenvironment (TME) of human cancers. Each model's unique biological and structural differences contribute to discrepancies in treatment responses, challenging the direct translation of experimental results to clinical settings. While 2D cell cultures are cost-effective and suitable for high-throughput screening, they lack the 3D architecture and cellular interactions of the in vivo TME. Organoids offer a more comprehensive 3D structure that better mirrors tumor heterogeneity, yet they still face limitations in fully mimicking in vivo conditions, such as vascularization and immune cell interactions. PDXs, although more representative of human cancers due to their genetic fidelity and TME preservation, are costly and resource-intensive, with human stromal and immune components gradually replaced by murine counterparts over time. This review assesses the strengths and limitations of each model, highlighting recent advancements in translational platforms that incorporate complex TME features. Understanding the influence of model selection on treatment efficacy predictions is essential for enhancing the reliability of preclinical findings and advancing personalized therapeutic strategies for GI cancers.
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Affiliation(s)
- Katarzyna Wawrzak-Pienkowska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowskiej MC 24A Street, 15-276, Bialystok, Poland; Department of Gastroenterology, Hepatology and Internal Diseases, Voivodeship Hospital in Bialystok, Sklodowskiej MC 26, 15-278, Bialystok, Poland
| | - Tomasz Pienkowski
- Clinical Research Center, Medical University of Bialystok, Sklodowskiej MC 24A, 15-276, Bialystok, Poland
| | - Anna Tankiewicz-Kwedlo
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222, Białystok, Poland
| | - Michal Ciborowski
- Clinical Research Center, Medical University of Bialystok, Sklodowskiej MC 24A, 15-276, Bialystok, Poland
| | - Krzysztof Kurek
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowskiej MC 24A Street, 15-276, Bialystok, Poland
| | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222, Białystok, Poland.
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9
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Zhu L, Yang W, Luo J, Lu D, Hu Y, Zhang R, Li Y, Qiu L, Chen Z, Chen L, Liu H. Comparison of characteristics and immune responses between paired human nasal and bronchial epithelial organoids. Cell Biosci 2025; 15:18. [PMID: 39920853 PMCID: PMC11806626 DOI: 10.1186/s13578-024-01342-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/18/2024] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND The nasal epithelium, as part of a continuous and integrated airway epithelium, provides a more accessible sample source than the bronchial epithelium. However, the similarities and differences in gene expression patterns and immune responses between these two sites have not been extensively studied. RESULTS Four lines of matched nasal and bronchial airway epithelial cells obtained from the four patients were embedded in Matrigel and cultured in thechemically defined medium to generate patient-derived nasal organoids (NO) and bronchial organoids (BO). Histologic examination of nasal organoid tissue revealed high similarity and a reduced ciliary beat frequency compared to bronchial organoid tissue. Whole exome sequencing revealed that over 99% of single nucleotides were shared between the NO and matched BO and there was a 95% overlap in their RNA transcriptomes. RNA sequencing analysis of differentially expressed genes indicated a significant reduction in the immune response in NO. RSV infection revealed more productive replication in NO, with a downregulated immune pathway identified by RNA sequencing analysis and upregulated levels of pro-inflammatory cytokines in culture supernatants in NO compared to BO. CONCLUSIONS NO and BO serve as robust in vitro models, faithfully recapitulating the biological characteristics of upper respiratory epithelial cells. The different regions of respiratory epithelial cells exhibit distinct immune responses, underscoring their complementary roles in exploring airway immune mechanisms and disease pathophysiology.
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Affiliation(s)
- Lu Zhu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Wenhao Yang
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Jiaxin Luo
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Danli Lu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yanan Hu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Rui Zhang
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yan Li
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Li Qiu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Zelian Chen
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Lina Chen
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China.
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Sichuan University, Chengdu, China.
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China.
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Sichuan University, Chengdu, China.
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
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10
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Kwon DH, Lim B, Lee SY, Won SH, Jang G. Establishment and characterization of endometrial organoids from different placental types. BMB Rep 2025; 58:95-103. [PMID: 39681412 PMCID: PMC11875743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/29/2024] [Accepted: 12/15/2024] [Indexed: 12/18/2024] Open
Abstract
Understanding molecular characteristics and metabolic processes of the mammalian endometrium is crucial for advancing biological research, particularly in veterinary obstetrics and pathology. This study established and analyzed organoids from endometrial epithelial stem cells of five mammals with different placental types: cows (cotyledonary), dogs and cats (zonary), pigs (diffuse), and rats (discoid). Organoids from these five species were maintained for over 13 passages, frozen, and thawed. Pathological analysis confirmed that they retained characteristics of their original tissues. Furthermore, integrative transcriptome analysis of organoids and tissues from the five species highlighted key pathways such as PI3K-Akt signaling and extracellular matrix-receptor interaction known to be crucial in cancer research. Although genes associated with vascular smooth muscle contraction were downregulated, these organoids exhibited significant activities of genes involved in hormone metabolism. In conclusion, our study achieved stable establishment of endometrial organoids from five mammals with different placental types, offering foundational data for organoid research. In the future, these organoids are suitable models for investigating uterine physiology and diseases and for developing potential therapies. [BMB Reports 2025; 58(2): 95-103].
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Affiliation(s)
- Dong-Hyeok Kwon
- Laboratory of Theriogenology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul 08826, Korea
- Comparative Medicine Disease Research Center, Seoul National University, Seoul 08826, Korea
| | - Byeonghwi Lim
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Sung-Yeon Lee
- Laboratory of Theriogenology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Sung-Ho Won
- Department of Public Health Sciences, Institute of Health & Environment, School of Public Health, Seoul National University, Seoul 08826, Korea
| | - Goo Jang
- Laboratory of Theriogenology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul 08826, Korea
- Comparative Medicine Disease Research Center, Seoul National University, Seoul 08826, Korea
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11
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Villarreal OE, Xu Y, Tran H, Machado A, Prescod D, Anderson A, Minelli R, Peoples M, Martinez AH, Lee HM, Wong CW, Fowlkes N, Kanikarla P, Sorokin A, Alshenaifi J, Coker O, Lin K, Bristow C, Viale A, Shen JP, Parseghian C, Marszalek JR, Corcoran R, Kopetz S. Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.22.634215. [PMID: 39896605 PMCID: PMC11785218 DOI: 10.1101/2025.01.22.634215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.
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12
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Zhang Y, Meng R, Sha D, Gao H, Wang S, Zhou J, Wang X, Li F, Li X, Song W. Advances in the application of colorectal cancer organoids in precision medicine. Front Oncol 2024; 14:1506606. [PMID: 39697234 PMCID: PMC11653019 DOI: 10.3389/fonc.2024.1506606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent gastrointestinal tumors globally and poses a significant threat to human health. In recent years, tumor organoids have emerged as ideal models for clinical disease research owing to their ability to closely mimic the original tumor tissue and maintain a stable phenotypic structure. Organoid technology has found widespread application in basic tumor research, precision therapy, and new drug development, establishing itself as a reliable preclinical model in CRC research. This has significantly advanced individualized and precise tumor therapies. Additionally, the integration of single-cell technology has enhanced the precision of organoid studies, offering deeper insights into tumor heterogeneity and treatment response, thereby contributing to the development of personalized treatment approaches. This review outlines the evolution of colorectal cancer organoid technology and highlights its strengths in modeling colorectal malignancies. This review also summarizes the progress made in precision tumor medicine and addresses the challenges in organoid research, particularly when organoid research is combined with single-cell technology. Furthermore, this review explores the future potential of organoid technology in the standardization of culture techniques, high-throughput screening applications, and single-cell multi-omics integration, offering novel directions for future colorectal cancer research.
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Affiliation(s)
- Yanan Zhang
- The First Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
- Department of Oncology, Zibo Hospital of Traditional Chinese Medicine, Zibo, China
| | - Ruoyu Meng
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Dan Sha
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Huiquan Gao
- Department of Radiotherapy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Shengxi Wang
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jun Zhou
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xiaoshan Wang
- The First Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Fuxia Li
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xinyu Li
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Wei Song
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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13
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Zhou S, Lin N, Yu L, Su X, Liu Z, Yu X, Gao H, Lin S, Zeng Y. Single-cell multi-omics in the study of digestive system cancers. Comput Struct Biotechnol J 2024; 23:431-445. [PMID: 38223343 PMCID: PMC10787224 DOI: 10.1016/j.csbj.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/07/2023] [Accepted: 12/07/2023] [Indexed: 01/16/2024] Open
Abstract
Digestive system cancers are prevalent diseases with a high mortality rate, posing a significant threat to public health and economic burden. The diagnosis and treatment of digestive system cancer confront conventional cancer problems, such as tumor heterogeneity and drug resistance. Single-cell sequencing (SCS) emerged at times required and has developed from single-cell RNA-seq (scRNA-seq) to the single-cell multi-omics era represented by single-cell spatial transcriptomics (ST). This article comprehensively reviews the advances of single-cell omics technology in the study of digestive system tumors. While analyzing and summarizing the research cases, vital details on the sequencing platform, sample information, sampling method, and key findings are provided. Meanwhile, we summarize the commonly used SCS platforms and their features, as well as the advantages of multi-omics technologies in combination. Finally, the development trends and prospects of the application of single-cell multi-omics technology in digestive system cancer research are prospected.
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Affiliation(s)
- Shuang Zhou
- The Second Clinical Medical School of Fujian Medical University, Quanzhou, Fujian Province, China
- The Clinical Center of Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Nanfei Lin
- The Clinical Center of Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Liying Yu
- The Clinical Center of Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Xiaoshan Su
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Zhenlong Liu
- Lady Davis Institute for Medical Research, Jewish General Hospital, & Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Xiaowan Yu
- Clinical Laboratory, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Hongzhi Gao
- The Clinical Center of Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
- Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Yiming Zeng
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
- Fujian Provincial Key Laboratory of Lung Stem Cells, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, China
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14
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Mondal S, Becskei A. Gene choice in cancer cells is exclusive in ion transport but concurrent in DNA replication. Comput Struct Biotechnol J 2024; 23:2534-2547. [PMID: 38974885 PMCID: PMC11226983 DOI: 10.1016/j.csbj.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/04/2024] [Accepted: 06/04/2024] [Indexed: 07/09/2024] Open
Abstract
Cancers share common cellular and physiological features. Little is known about whether distinctive gene expression patterns can be displayed at the single-cell level by gene families in cancer cells. The expression of gene homologs within a family can exhibit concurrence and exclusivity. Concurrence can promote all-or-none expression patterns of related genes and underlie alternative physiological states. Conversely, exclusive gene families express the same or similar number of homologs in each cell, allowing a broad repertoire of cell identities to be generated. We show that gene families involved in the cell-cycle and antigen presentation are expressed concurrently. Concurrence in the DNA replication complex MCM reflects the replicative status of cells, including cell lines and cancer-derived organoids. Exclusive expression requires precise regulatory mechanism, but cancer cells retain this form of control for ion homeostasis and extend it to gene families involved in cell migration. Thus, the cell adhesion-based identity of healthy cells is transformed to an identity based on migration in the population of cancer cells, reminiscent of epithelial-mesenchymal transition.
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Affiliation(s)
- Samuel Mondal
- Biozentrum, University of Basel, Spitalstrasse 41, Basel 4056, Switzerland
| | - Attila Becskei
- Biozentrum, University of Basel, Spitalstrasse 41, Basel 4056, Switzerland
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15
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Xuan Z, Zhang Y, Li D, Wang K, Huang P, Shi J. PLXNB1/SEMA4D signals mediate interactions between malignant epithelial and immune cells to promote colorectal cancer liver metastasis. J Cell Mol Med 2024; 28:e70142. [PMID: 39443302 PMCID: PMC11499074 DOI: 10.1111/jcmm.70142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/01/2024] [Accepted: 10/01/2024] [Indexed: 10/25/2024] Open
Abstract
Distal metastases result from metastatic microenvironment and tumour epithelial cell interactions, the cellular heterogeneity of primary colorectal cancer (CRC) and liver metastases (LM) was evaluated by integrating single-cell sequencing data, and the collected gene expression data from metastatic epithelial cell subsets was used to construct a prognostic model and to identify intercellular receptor-ligand interactions between epithelial and immune cells in CRC and LM. Multiplex immunofluorescence staining, and in vitro wound healing, cell migration and cell apoptosis assays were performed to further explore the biological relevance of identified potential regulatory molecules. In this study, approximately 17 epithelial cell subtypes were detected, with Epi-11 cells being highly expressed in LM tissues compared with CRC samples. Furthermore, patients with high expression of the metastasis-related genetic profile of Epi-11 had a poorer prognosis. By predicting receptor-ligand interactions, Epi-11 cells were found to interact more with myeloid and T/natural killer cells in LM tissues when compared to primary CRC samples, which was mediated by the PLXNB1/SEMA4D axis. In addition, high SEMA4D expression was correlated with decreased overall survival of patients with CRC, whereas PLXNB1 was not. SEMA4D knockdown prevented the migration and promoted the apoptosis of HCT116 cells in vitro. In summary, Epi-11 cells, an important subset of epithelial cells, may drive the LM of CRC and act by crosstalk with immune cells through the PLXNB1/SEMA4D signalling axis.
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Affiliation(s)
- Zixue Xuan
- Center for Clinical Pharmacy, Cancer Center, Department of PharmacyZhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeZhejiangHangzhouChina
- Department of PharmacyZhejiang Provincial People's Hospital Bijie HospitalBijieGuizhouChina
| | - Yuan Zhang
- Department of PharmacyZhejiang Provincial People's Hospital Bijie HospitalBijieGuizhouChina
| | - Dan Li
- Department of PharmacyZhejiang Provincial People's Hospital Bijie HospitalBijieGuizhouChina
| | - Kai Wang
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical MedicineSouthwest Medical UniversityLuzhouSichuanChina
| | - Ping Huang
- Center for Clinical Pharmacy, Cancer Center, Department of PharmacyZhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeZhejiangHangzhouChina
- Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceZhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeZhejiangHangzhouChina
| | - Jiana Shi
- Center for Clinical Pharmacy, Cancer Center, Department of PharmacyZhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeZhejiangHangzhouChina
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16
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Duan L, Xia Y, Fan R, Shuai Y, Li C, Hou X. Prognostic aging gene-based score for colorectal cancer: unveiling links to drug resistance, mutation burden, and personalized treatment strategies. Discov Oncol 2024; 15:454. [PMID: 39287898 PMCID: PMC11408439 DOI: 10.1007/s12672-024-01350-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 09/13/2024] [Indexed: 09/19/2024] Open
Abstract
OBJECTIVE Colorectal cancer (CRC) is characterized by high incidence and mortality rates worldwide. In this study, we present a novel aging-related gene-based risk scoring system (Aging score) as a predictive tool for CRC prognosis. METHOD We identified prognostic aging-related genes using univariate Cox regression analysis, revealing key biological processes in CRC progression. We then constructed a robust prognostic model using LASSO and multivariate Cox regression analyses, including four critical genes: CAV1, FOXM1, MAD2L1, and WT1. RESULT The Aging score demonstrated high prognostic performance across the training, testing, and entire TCGA-CRC datasets, proving its reliability. High-risk patients identified by the Aging score had significantly shorter overall survival times than low-risk patients, indicating its potential for patient stratification and personalized treatment. The Aging score remained an independent prognostic factor compared to age, gender, and tumor stage. Additionally, the score was linked to tumor mutation burden and microsatellite instability, indicators of immune checkpoint inhibitor response. High-risk patients also showed higher estimated IC50 values for common chemotherapeutic drugs, suggesting possible treatment resistance. CONCLUSION Our findings highlight the Aging score's potential to enhance clinical decision-making and pave the way for personalized CRC management.
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Affiliation(s)
- Ling Duan
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
| | - Yang Xia
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Department of Hematology, The First People's Hospital of Lanzhou, Lanzhou, Gansu, China
| | - Rui Fan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
| | - Yuxi Shuai
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
| | - Chunmei Li
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaoming Hou
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China.
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17
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Lee H, Yang S, Lee KJ, Kim SN, Jeong JS, Kim KY, Jung CR, Jeon S, Kwon D, Lee S, Lee H, Park C, Ahn SJ, Yoo J, Son MY. Standardization and quality assessment for human intestinal organoids. Front Cell Dev Biol 2024; 12:1383893. [PMID: 39329062 PMCID: PMC11424408 DOI: 10.3389/fcell.2024.1383893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/02/2024] [Indexed: 09/28/2024] Open
Abstract
To enhance the practical application of intestinal organoids, it is imperative to establish standardized guidelines. This proposed standardization outlines a comprehensive framework to ensure consistency and reliability in the development, characterization, and application of intestinal organoids. The recommended guidelines encompass crucial parameters, including culture conditions, critical quality attributes, quality control measures, and functional assessments, aimed at fostering a standardized approach across diverse research initiatives. The implementation of these guidelines is anticipated to significantly contribute to the reproducibility and comparability of results in the burgeoning field of intestinal organoid research.
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Affiliation(s)
- Hana Lee
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Seunghye Yang
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- ORGANOIDSCIENCES, Seongnam-si, Republic of Korea
| | - Kyung Jin Lee
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- ORGANOIDSCIENCES, Seongnam-si, Republic of Korea
| | - Si-Na Kim
- ORGANOIDSCIENCES, Seongnam-si, Republic of Korea
| | - Ji-Seon Jeong
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- Korea Research Institute of Standards and Science (KRISS), Daejeon, Republic of Korea
| | - Ki Young Kim
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Cho-Rok Jung
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Sooyeon Jeon
- Digital Health Laboratory, Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Dayeon Kwon
- Digital Health Laboratory, Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Sungin Lee
- Digital Health Laboratory, Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Hanbyeol Lee
- Digital Health Laboratory, Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Chihye Park
- Digital Health Laboratory, Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Sun-Ju Ahn
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- Digital Health Laboratory, Department of Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jongman Yoo
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- ORGANOIDSCIENCES, Seongnam-si, Republic of Korea
- Department of Microbiology, CHA University School of Medicine, Seongnam-si, Republic of Korea
| | - Mi-Young Son
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Organoid Standards Initiative (OSI), Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea
- KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
- Department of Biological Science, Sungkyunkwan University, Suwon, Republic of Korea
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18
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Xin M, Li Q, Wang D, Wang Z. Organoids for Cancer Research: Advances and Challenges. Adv Biol (Weinh) 2024; 8:e2400056. [PMID: 38977414 DOI: 10.1002/adbi.202400056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/04/2024] [Indexed: 07/10/2024]
Abstract
As 3D culture technology advances, new avenues have opened for the development of physiological human cancer models. These preclinical models provide efficient ways to translate basic cancer research into clinical tumor therapies. Recently, cancer organoids have emerged as a model to dissect the more complex tumor microenvironment. Incorporating cancer organoids into preclinical programs have the potential to increase the success rate of oncology drug development and recapitulate the most efficacious treatment regimens for cancer patients. In this review, four main types of cancer organoids are introduced, their applications, advantages, limitations, and prospects are discussed, as well as the recent application of single-cell RNA-sequencing (scRNA-seq) in exploring cancer organoids to advance this field.
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Affiliation(s)
- Miaomaio Xin
- Assisted Reproductive Center, Women's & Children's Hospital of Northwest, Xi'an, Shanxi Province, 710000, China
- University of South Bohemia in Ceske Budejovice, Vodnany, 38925, Czech Republic
| | - Qian Li
- Changsha Medical University, Changsha, Hunan Province, 410000, China
| | - Dongyang Wang
- Assisted Reproductive Center, Women's & Children's Hospital of Northwest, Xi'an, Shanxi Province, 710000, China
| | - Zheng Wang
- Medical Center of Hematology, the Second Affiliated Hospital, Army Medical University, Chongqing, Sichuan Province, 404100, China
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19
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Yan H, Wu T, Li X, Feng Z, Ge M, Zhang L, Dong WF. Establishment of the microscope incubation system and its application in evaluating tumor treatment effects through real-time live cellular imaging. Front Bioeng Biotechnol 2024; 12:1447265. [PMID: 39219621 PMCID: PMC11362064 DOI: 10.3389/fbioe.2024.1447265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024] Open
Abstract
Introduction: Long-term imaging of live cells is commonly used for the study of dynamic cell behaviors. It is crucial to keep the cell viability during the investigation of physiological and biological processes by live cell imaging. Conventional incubators that providing stable temperature, carbon dioxide (CO2) concentration, and humidity are often incompatible with most imaging tools. Available commercial or custom-made stage-top incubators are bulky or unable to provide constant environmental conditions during long time culture. Methods: In this study, we reported the development of the microscope incubation system (MIS) that can be easily adapted to any inverted microscope stage. Incremental PID control algorithm was introduced to keep stable temperature and gas concentration of the system. Moreover, efficient translucent materials were applied for the top and bottom of the incubator which make it possible for images taken during culture. Results: The MIS could support cell viability comparable to standard incubators. When used in real time imaging, the MIS was able to trace single cell migration in scratch assay, T cell mediated tumor cells killing in co-culture assay, inflation-collapse and fusion of organoids in 3D culture. And the viability and drug responses of cells cultured in the MIS were able to be calculated by a label-free methods based on long term imaging. Discussion: We offer new insights into monitoring cell behaviors during long term culture by using the stage adapted MIS. This study illustrates that the newly developed MIS is a viable solution for long-term imaging during in vitro cell culture and demonstrates its potential in cell biology, cancer biology and drug discovery research where long-term real-time recording is required.
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Affiliation(s)
- Haiyang Yan
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou, China
| | - Tong Wu
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou, China
| | - Xinlu Li
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou, China
| | - Zhengyang Feng
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Mingfeng Ge
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou, China
- Zhengzhou Institute of Biomedical Engineering and Technology, Zhengzhou, China
| | - Lixing Zhang
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou, China
| | - Wen-Fei Dong
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou, China
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van der Graaff D, Seghers S, Vanclooster P, Deben C, Vandamme T, Prenen H. Advancements in Research and Treatment Applications of Patient-Derived Tumor Organoids in Colorectal Cancer. Cancers (Basel) 2024; 16:2671. [PMID: 39123399 PMCID: PMC11311786 DOI: 10.3390/cancers16152671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/20/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant health burden globally, being the second leading cause of cancer-related mortality. Despite significant therapeutic advancements, resistance to systemic antineoplastic agents remains an important obstacle, highlighting the need for innovative screening tools to tailor patient-specific treatment. This review explores the application of patient-derived tumor organoids (PDTOs), three-dimensional, self-organizing models derived from patient tumor samples, as screening tools for drug resistance in CRC. PDTOs offer unique advantages over traditional models by recapitulating the tumor architecture, cellular heterogeneity, and genomic landscape and are a valuable ex vivo predictive drug screening tool. This review provides an overview of the current literature surrounding the use of PDTOs as an instrument for predicting therapy responses in CRC. We also explore more complex models, such as co-cultures with important stromal cells, such as cancer-associated fibroblasts, and organ-on-a-chip models. Furthermore, we discuss the use of PDTOs for drug repurposing, offering a new approach to identify the existing drugs effective against drug-resistant CRC. Additionally, we explore how PDTOs serve as models to gain insights into drug resistance mechanisms, using newer techniques, such as single-cell RNA sequencing and CRISPR-Cas9 genome editing. Through this review, we aim to highlight the potential of PDTOs in advancing our understanding of predicting therapy responses, drug resistance, and biomarker identification in CRC management.
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Affiliation(s)
| | - Sofie Seghers
- Department of Medical Oncology, University Hospital Antwerp, 2650 Edegem, Belgium
- Center for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, Belgium
| | | | - Christophe Deben
- Center for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, Belgium
| | - Timon Vandamme
- Department of Medical Oncology, University Hospital Antwerp, 2650 Edegem, Belgium
- Center for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, Belgium
| | - Hans Prenen
- Department of Medical Oncology, University Hospital Antwerp, 2650 Edegem, Belgium
- Center for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, Belgium
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21
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Long Q, Zhang P, Ou Y, Li W, Yan Q, Yuan X. Single-cell sequencing advances in research on mesenchymal stem/stromal cells. Hum Cell 2024; 37:904-916. [PMID: 38743204 DOI: 10.1007/s13577-024-01076-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 05/04/2024] [Indexed: 05/16/2024]
Abstract
Mesenchymal stem/stromal cells (MSCs), originating from the mesoderm, represent a multifunctional stem cell population capable of differentiating into diverse cell types and exhibiting a wide range of biological functions. Despite more than half a century of research, MSCs continue to be among the most extensively studied cell types in clinical research projects globally. However, their significant heterogeneity and phenotypic instability have significantly hindered their exploration and application. Single-cell sequencing technology emerges as a powerful tool to address these challenges, offering precise dissection of complex cellular samples. It uncovers the genetic structure and gene expression status of individual contained cells on a massive scale and reveals the heterogeneity among these cells. It links the molecular characteristics of MSCs with their clinical applications, contributing to the advancement of regenerative medicine. With the development and cost reduction of single-cell analysis techniques, sequencing technology is now widely applied in fundamental research and clinical trials. This study aimed to review the application of single-cell sequencing in MSC research and assess its prospects.
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Affiliation(s)
- Qingxi Long
- Department of Neurology, Kailuan General Hospital, Affiliated North China University of Science and Technology, Tangshan, 063000, China
| | - Pingshu Zhang
- Department of Neurology, Kailuan General Hospital, Affiliated North China University of Science and Technology, Tangshan, 063000, China
- Hebei Provincial Key Laboratory of Neurobiological Function, Tangshan, 063000, China
| | - Ya Ou
- Department of Neurology, Kailuan General Hospital, Affiliated North China University of Science and Technology, Tangshan, 063000, China
- Hebei Provincial Key Laboratory of Neurobiological Function, Tangshan, 063000, China
| | - Wen Li
- Department of Neurology, Kailuan General Hospital, Affiliated North China University of Science and Technology, Tangshan, 063000, China
| | - Qi Yan
- Department of Neurology, Kailuan General Hospital, Affiliated North China University of Science and Technology, Tangshan, 063000, China
| | - Xiaodong Yuan
- Department of Neurology, Kailuan General Hospital, Affiliated North China University of Science and Technology, Tangshan, 063000, China.
- Hebei Provincial Key Laboratory of Neurobiological Function, Tangshan, 063000, China.
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22
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Zhang JP, Yan BZ, Liu J, Wang W. Action of circulating and infiltrating B cells in the immune microenvironment of colorectal cancer by single-cell sequencing analysis. World J Gastrointest Oncol 2024; 16:2671-2684. [DOI: 10.4251/wjgo.v16.i6.2671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/10/2024] [Accepted: 04/09/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND The complexity of the immune microenvironment has an impact on the treatment of colorectal cancer (CRC), one of the most prevalent malignancies worldwide. In this study, multi-omics and single-cell sequencing techniques were used to investigate the mechanism of action of circulating and infiltrating B cells in CRC. By revealing the heterogeneity and functional differences of B cells in cancer immunity, we aim to deepen our understanding of immune regulation and provide a scientific basis for the development of more effective cancer treatment strategies.
AIM To explore the role of circulating and infiltrating B cell subsets in the immune microenvironment of CRC, explore the potential driving mechanism of B cell development, analyze the interaction between B cells and other immune cells in the immune microenvironment and the functions of communication molecules, and search for possible regulatory pathways to promote the anti-tumor effects of B cells.
METHODS A total of 69 paracancer (normal), tumor and peripheral blood samples were collected from 23 patients with CRC from The Cancer Genome Atlas database (https://portal.gdc.cancer.gov/). After the immune cells were sorted by multicolor flow cytometry, the single cell transcriptome and B cell receptor group library were sequenced using the 10X Genomics platform, and the data were analyzed using bioinformatics tools such as Seurat. The differences in the number and function of B cell infiltration between tumor and normal tissue, the interaction between B cell subsets and T cells and myeloid cell subsets, and the transcription factor regulatory network of B cell subsets were explored and analyzed.
RESULTS Compared with normal tissue, the infiltrating number of CD20+B cell subsets in tumor tissue increased significantly. Among them, germinal center B cells (GCB) played the most prominent role, with positive clone expansion and heavy chain mutation level increasing, and the trend of differentiation into memory B cells increased. However, the number of plasma cells in the tumor microenvironment decreased significantly, and the plasma cells secreting IgA antibodies decreased most obviously. In addition, compared with the immune microenvironment of normal tissues, GCB cells in tumor tissues became more closely connected with other immune cells such as T cells, and communication molecules that positively regulate immune function were significantly enriched.
CONCLUSION The role of GCB in CRC tumor microenvironment is greatly enhanced, and its affinity to tumor antigen is enhanced by its significantly increased heavy chain mutation level. Meanwhile, GCB has enhanced its association with immune cells in the microenvironment, which plays a positive anti-tumor effect.
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Affiliation(s)
- Jing-Po Zhang
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Hebei Medical University, Shijiazhuang 050032, Hebei Province, China
| | - Bing-Zheng Yan
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Hebei Medical University, Shijiazhuang 050032, Hebei Province, China
| | - Jie Liu
- Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha 410002, Hunan Province, China
| | - Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Hebei Medical University, Shijiazhuang 050032, Hebei Province, China
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Zhang JP, Yan BZ, Liu J, Wang W. Action of circulating and infiltrating B cells in the immune microenvironment of colorectal cancer by single-cell sequencing analysis. World J Gastrointest Oncol 2024; 16:2683-2696. [PMID: 38994150 PMCID: PMC11236258 DOI: 10.4251/wjgo.v16.i6.2683] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/10/2024] [Accepted: 04/09/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND The complexity of the immune microenvironment has an impact on the treatment of colorectal cancer (CRC), one of the most prevalent malignancies worldwide. In this study, multi-omics and single-cell sequencing techniques were used to investigate the mechanism of action of circulating and infiltrating B cells in CRC. By revealing the heterogeneity and functional differences of B cells in cancer immunity, we aim to deepen our understanding of immune regulation and provide a scientific basis for the development of more effective cancer treatment strategies. AIM To explore the role of circulating and infiltrating B cell subsets in the immune microenvironment of CRC, explore the potential driving mechanism of B cell development, analyze the interaction between B cells and other immune cells in the immune microenvironment and the functions of communication molecules, and search for possible regulatory pathways to promote the anti-tumor effects of B cells. METHODS A total of 69 paracancer (normal), tumor and peripheral blood samples were collected from 23 patients with CRC from The Cancer Genome Atlas database (https://portal.gdc.cancer.gov/). After the immune cells were sorted by multicolor flow cytometry, the single cell transcriptome and B cell receptor group library were sequenced using the 10X Genomics platform, and the data were analyzed using bioinformatics tools such as Seurat. The differences in the number and function of B cell infiltration between tumor and normal tissue, the interaction between B cell subsets and T cells and myeloid cell subsets, and the transcription factor regulatory network of B cell subsets were explored and analyzed. RESULTS Compared with normal tissue, the infiltrating number of CD20+B cell subsets in tumor tissue increased significantly. Among them, germinal center B cells (GCB) played the most prominent role, with positive clone expansion and heavy chain mutation level increasing, and the trend of differentiation into memory B cells increased. However, the number of plasma cells in the tumor microenvironment decreased significantly, and the plasma cells secreting IgA antibodies decreased most obviously. In addition, compared with the immune microenvironment of normal tissues, GCB cells in tumor tissues became more closely connected with other immune cells such as T cells, and communication molecules that positively regulate immune function were significantly enriched. CONCLUSION The role of GCB in CRC tumor microenvironment is greatly enhanced, and its affinity to tumor antigen is enhanced by its significantly increased heavy chain mutation level. Meanwhile, GCB has enhanced its association with immune cells in the microenvironment, which plays a positive anti-tumor effect.
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Affiliation(s)
- Jing-Po Zhang
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Hebei Medical University, Shijiazhuang 050032, Hebei Province, China
| | - Bing-Zheng Yan
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Hebei Medical University, Shijiazhuang 050032, Hebei Province, China
| | - Jie Liu
- Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha 410002, Hunan Province, China
| | - Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Hebei Medical University, Shijiazhuang 050032, Hebei Province, China
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24
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Guan R, Li C, Gu F, Li W, Wei D, Cao S, Chang F, Lei D. Single-cell transcriptomic landscape and the microenvironment of normal adjacent tissues in hypopharyngeal carcinoma. BMC Genomics 2024; 25:489. [PMID: 38760729 PMCID: PMC11100249 DOI: 10.1186/s12864-024-10321-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/18/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND The cellular origin of hypopharyngeal diseases is crucial for further diagnosis and treatment, and the microenvironment in tissues may also be associated with specific cell types at the same time. Normal adjacent tissues (NATs) of hypopharyngeal carcinoma differ from non-tumor-bearing tissues, and can influenced by the tumor. However, the heterogeneity in kinds of disease samples remains little known, and the transcriptomic profile about biological information associated with disease occurrence and clinical outcome contained in it has yet to be fully evaluated. For these reasons, we should quickly investigate the taxonomic and transcriptomic information of NATs in human hypopharynx. RESULTS Single-cell suspensions of normal adjacent tissues (NATs) of hypopharyngeal carcinoma were obtained and single-cell RNA sequencing (scRNA-seq) was performed. We present scRNA-seq data from 39,315 high-quality cells in the hypopharyngeal from five human donors, nine clusters of normal adjacent human hypopharyngeal cells were presented, including epithelial cells, endothelial cells (ECs), mononuclear phagocyte system cells (MPs), fibroblasts, T cells, plasma cells, B cells, mural cells and mast cells. Nonimmune components in the microenvironment, including epithelial cells, endothelial cells, fibroblasts and the subpopulations of them were performed. CONCLUSIONS Our data provide a solid basis for the study of single-cell landscape in human normal adjacent hypopharyngeal tissues biology and related diseases.
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Affiliation(s)
- Rui Guan
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China
- Cheeloo College of Medicine, Shandong University, Jinan , Shandong, 250012, China
| | - Ce Li
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China
| | - Fangmeng Gu
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China
| | - Wenming Li
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China
| | - Dongmin Wei
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China
| | - Shengda Cao
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China
| | - Fen Chang
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China
| | - Dapeng Lei
- Department of Otorhinolaryngology, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Shandong, 250012, China.
- Cheeloo College of Medicine, Shandong University, Jinan , Shandong, 250012, China.
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Tan R, Zhang Z, Ding P, Liu Y, Liu H, Lu M, Chen YG. A growth factor-reduced culture system for colorectal cancer organoids. Cancer Lett 2024; 588:216737. [PMID: 38382667 DOI: 10.1016/j.canlet.2024.216737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 02/06/2024] [Accepted: 02/16/2024] [Indexed: 02/23/2024]
Abstract
Although organoids derived from tumor tissues have been widely used in cancer research, it is a great challenge for cultured organoids to retain the characteristics of the original tumor tissues due to their heterogeneity. In this study, we explore organoid culture recipes to capture tumor features of colorectal cancers. We find that the activation of Wnt and EGF signaling and inhibition of BMP signaling are non-essential for the survival of most colorectal cancer organoids (CRCOs). We design a growth factor-reduced culture medium containing FGF10, A83-01 (TGF-β type I receptor inhibitor), SB202190 (p38 MAPK inhibitor), gastrin, and nicotinamide. Using this medium, we can maintain tumor features in long-term CRCO cultivation, as evidenced by histopathology, genetic stability, tumorigenicity, and response of clinical treatments. Our findings offer a reliable and economical strategy for CRCO culture, facilitating the utilization of organoids in colorectal cancer research and treatment.
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Affiliation(s)
- Ronghui Tan
- Graduate School of Guangzhou Medical University, Guangzhou, 511436, China; Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Ze Zhang
- Guangzhou National Laboratory, Guangzhou, 510005, China; Institute of Biomedical Research, Yunnan University, Kunming, 650500, China
| | - Peirong Ding
- Department of Colorectal Cancer, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Yue Liu
- Guangzhou National Laboratory, Guangzhou, 510005, China; Institute of Biomedical Research, Yunnan University, Kunming, 650500, China
| | - Huidong Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Minyi Lu
- Huayi Regeneration Technology Limited Liability Company, Guangzhou, 510005, China
| | - Ye-Guang Chen
- Guangzhou National Laboratory, Guangzhou, 510005, China; The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
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Ahmad Zawawi SS, Salleh EA, Musa M. Spheroids and organoids derived from colorectal cancer as tools for in vitro drug screening. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:409-431. [PMID: 38745769 PMCID: PMC11090692 DOI: 10.37349/etat.2024.00226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/02/2024] [Indexed: 05/16/2024] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease. Conventional two-dimensional (2D) culture employing cell lines was developed to study the molecular properties of CRC in vitro. Although these cell lines which are isolated from the tumor niche in which cancer develop, the translation to human model such as studying drug response is often hindered by the inability of cell lines to recapture original tumor features and the lack of heterogeneous clinical tumors represented by this 2D model, differed from in vivo condition. These limitations which may be overcome by utilizing three-dimensional (3D) culture consisting of spheroids and organoids. Over the past decade, great advancements have been made in optimizing culture method to establish spheroids and organoids of solid tumors including of CRC for multiple purposes including drug screening and establishing personalized medicine. These structures have been proven to be versatile and robust models to study CRC progression and deciphering its heterogeneity. This review will describe on advances in 3D culture technology and the application as well as the challenges of CRC-derived spheroids and organoids as a mode to screen for anticancer drugs.
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Affiliation(s)
| | - Elyn Amiela Salleh
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Marahaini Musa
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
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27
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Rezapour M, Walker SJ, Ornelles DA, McNutt PM, Atala A, Gurcan MN. Analysis of gene expression dynamics and differential expression in viral infections using generalized linear models and quasi-likelihood methods. Front Microbiol 2024; 15:1342328. [PMID: 38655085 PMCID: PMC11037428 DOI: 10.3389/fmicb.2024.1342328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Introduction Our study undertakes a detailed exploration of gene expression dynamics within human lung organ tissue equivalents (OTEs) in response to Influenza A virus (IAV), Human metapneumovirus (MPV), and Parainfluenza virus type 3 (PIV3) infections. Through the analysis of RNA-Seq data from 19,671 genes, we aim to identify differentially expressed genes under various infection conditions, elucidating the complexities of virus-host interactions. Methods We employ Generalized Linear Models (GLMs) with Quasi-Likelihood (QL) F-tests (GLMQL) and introduce the novel Magnitude-Altitude Score (MAS) and Relaxed Magnitude-Altitude Score (RMAS) algorithms to navigate the intricate landscape of RNA-Seq data. This approach facilitates the precise identification of potential biomarkers, highlighting the host's reliance on innate immune mechanisms. Our comprehensive methodological framework includes RNA extraction, library preparation, sequencing, and Gene Ontology (GO) enrichment analysis to interpret the biological significance of our findings. Results The differential expression analysis unveils significant changes in gene expression triggered by IAV, MPV, and PIV3 infections. The MAS and RMAS algorithms enable focused identification of biomarkers, revealing a consistent activation of interferon-stimulated genes (e.g., IFIT1, IFIT2, IFIT3, OAS1) across all viruses. Our GO analysis provides deep insights into the host's defense mechanisms and viral strategies exploiting host cellular functions. Notably, changes in cellular structures, such as cilium assembly and mitochondrial ribosome assembly, indicate a strategic shift in cellular priorities. The precision of our methodology is validated by a 92% mean accuracy in classifying respiratory virus infections using multinomial logistic regression, demonstrating the superior efficacy of our approach over traditional methods. Discussion This study highlights the intricate interplay between viral infections and host gene expression, underscoring the need for targeted therapeutic interventions. The stability and reliability of the MAS/RMAS ranking method, even under stringent statistical corrections, and the critical importance of adequate sample size for biomarker reliability are significant findings. Our comprehensive analysis not only advances our understanding of the host's response to viral infections but also sets a new benchmark for the identification of biomarkers, paving the way for the development of effective diagnostic and therapeutic strategies.
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Affiliation(s)
- Mostafa Rezapour
- Center for Artificial Intelligence Research, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Stephen J. Walker
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - David A. Ornelles
- Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Patrick M. McNutt
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Metin Nafi Gurcan
- Center for Artificial Intelligence Research, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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Yan S, He Y, Zhu Y, Ye W, Chen Y, Zhu C, Zhan F, Ma Z. Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research. Front Cell Dev Biol 2024; 12:1384450. [PMID: 38638528 PMCID: PMC11024315 DOI: 10.3389/fcell.2024.1384450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/22/2024] [Indexed: 04/20/2024] Open
Abstract
Gastrointestinal cancers account for approximately one-third of the total global cancer incidence and mortality with a poor prognosis. It is one of the leading causes of cancer-related deaths worldwide. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. As a novel preclinical model, tumor patient-derived organoids (PDOs), can be established from patients' tumor tissue and cultured in the laboratory in 3D architectures. This 3D model can not only highly simulate and preserve key biological characteristics of the source tumor tissue in vitro but also reproduce the in vivo tumor microenvironment through co-culture. Our review provided an overview of the different in vitro models in current tumor research, the derivation of cells in PDO models, and the application of PDO model technology in gastrointestinal cancers, particularly the applications in combination with CRISPR/Cas9 gene editing technology, tumor microenvironment simulation, drug screening, drug development, and personalized medicine. It also elucidates the ethical status quo of organoid research and the current challenges encountered in clinical research, and offers a forward-looking assessment of the potential paths for clinical organoid research advancement.
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Affiliation(s)
- Sicheng Yan
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuxuan He
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuehong Zhu
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wangfang Ye
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Chen
- Department of Colorectal Surgery, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, China
| | - Cong Zhu
- Department of Colorectal Surgery, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, China
| | - Fuyuan Zhan
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhihong Ma
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
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Mao Y, Wang W, Yang J, Zhou X, Lu Y, Gao J, Wang X, Wen L, Fu W, Tang F. Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids. Protein Cell 2024; 15:285-304. [PMID: 37345888 PMCID: PMC10984622 DOI: 10.1093/procel/pwad038] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/22/2023] [Indexed: 06/23/2023] Open
Abstract
Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.
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Affiliation(s)
- Yunuo Mao
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
- The Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Wei Wang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Jingwei Yang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Xin Zhou
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Peking University Third Hospital Cancer Center, Beijing 100871, China
| | - Yongqu Lu
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Peking University Third Hospital Cancer Center, Beijing 100871, China
| | - Junpeng Gao
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Xiao Wang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
| | - Lu Wen
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Wei Fu
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Peking University Third Hospital Cancer Center, Beijing 100871, China
| | - Fuchou Tang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Jose A, Kulkarni P, Thilakan J, Munisamy M, Malhotra AG, Singh J, Kumar A, Rangnekar VM, Arya N, Rao M. Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine. Mol Cancer 2024; 23:50. [PMID: 38461268 PMCID: PMC10924370 DOI: 10.1186/s12943-023-01916-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 12/15/2023] [Indexed: 03/11/2024] Open
Abstract
Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.
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Affiliation(s)
- Anmi Jose
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Pallavi Kulkarni
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Jaya Thilakan
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Murali Munisamy
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Anvita Gupta Malhotra
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Jitendra Singh
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Vivek M Rangnekar
- Markey Cancer Center and Department of Radiation Medicine, University of Kentucky, Lexington, KY, 40536, USA
| | - Neha Arya
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India.
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Zhao L, Wang Q, Yang C, Ye Y, Shen Z. Application of Single-Cell Sequencing Technology in Research on Colorectal Cancer. J Pers Med 2024; 14:108. [PMID: 38248808 PMCID: PMC10820918 DOI: 10.3390/jpm14010108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/04/2024] [Accepted: 01/10/2024] [Indexed: 01/23/2024] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent and second most lethal cancer globally, with gene mutations and tumor metastasis contributing to its poor prognosis. Single-cell sequencing technology enables high-throughput analysis of the genome, transcriptome, and epigenetic landscapes at the single-cell level. It offers significant insights into analyzing the tumor immune microenvironment, detecting tumor heterogeneity, exploring metastasis mechanisms, and monitoring circulating tumor cells (CTCs). This article provides a brief overview of the technical procedure and data processing involved in single-cell sequencing. It also reviews the current applications of single-cell sequencing in CRC research, aiming to enhance the understanding of intratumoral heterogeneity, CRC development, CTCs, and novel drug targets. By exploring the diverse molecular and clinicopathological characteristics of tumor heterogeneity using single-cell sequencing, valuable insights can be gained into early diagnosis, therapy, and prognosis of CRC. Thus, this review serves as a valuable resource for identifying prognostic markers, discovering new therapeutic targets, and advancing personalized therapy in CRC.
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Affiliation(s)
- Long Zhao
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (L.Z.); (C.Y.); (Y.Y.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Quan Wang
- Department of Ambulatory Surgery Center, Xijing Hospital, Air Force Military Medical University, Xi’an 710032, China;
| | - Changjiang Yang
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (L.Z.); (C.Y.); (Y.Y.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Yingjiang Ye
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (L.Z.); (C.Y.); (Y.Y.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Zhanlong Shen
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (L.Z.); (C.Y.); (Y.Y.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
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32
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Xiu Z, Yang Q, Xie F, Han F, He W, Liao W. Revolutionizing digestive system tumor organoids research: Exploring the potential of tumor organoids. J Tissue Eng 2024; 15:20417314241255470. [PMID: 38808253 PMCID: PMC11131411 DOI: 10.1177/20417314241255470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 05/02/2024] [Indexed: 05/30/2024] Open
Abstract
Digestive system tumors are the leading cause of cancer-related deaths worldwide. Despite ongoing research, our understanding of their mechanisms and treatment remain inadequate. One promising tool for clinical applications is the use of gastrointestinal tract tumor organoids, which serve as an important in vitro model. Tumor organoids exhibit a genotype similar to the patient's tumor and effectively mimic various biological processes, including tissue renewal, stem cell, and ecological niche functions, and tissue response to drugs, mutations, or injury. As such, they are valuable for drug screening, developing novel drugs, assessing patient outcomes, and supporting immunotherapy. In addition, innovative materials and techniques can be used to optimize tumor organoid culture systems. Several applications of digestive system tumor organoids have been described and have shown promising results in related aspects. In this review, we discuss the current progress, limitations, and prospects of this model for digestive system tumors.
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Affiliation(s)
- Zhian Xiu
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Qian Yang
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fusheng Xie
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Feng Han
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Weiwei He
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Weifang Liao
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
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33
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Erfanian N, Nasseri S, Miraki Feriz A, Safarpour H, Namaei MH. Characterization of Wnt signaling pathway under treatment of Lactobacillus acidophilus postbiotic in colorectal cancer using an integrated in silico and in vitro analysis. Sci Rep 2023; 13:22988. [PMID: 38151510 PMCID: PMC10752892 DOI: 10.1038/s41598-023-50047-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 12/14/2023] [Indexed: 12/29/2023] Open
Abstract
Colorectal cancer (CRC) is a prevalent and life-threatening cancer closely associated with the gut microbiota. Probiotics, as a vital microbiota group, interact with the host's colonic epithelia and immune cells by releasing a diverse range of metabolites named postbiotics. The present study examined the effects of postbiotics on CRC's prominent differentially expressed genes (DEGs) using in silico and in vitro analysis. Through single-cell RNA sequencing (scRNA-seq), we identified four DEGs in CRC, including secreted frizzled-related protein 1 (SFRP1), secreted frizzled-related protein 2 (SFRP2), secreted frizzled-related protein 4 (SFRP4), and matrix metallopeptidase 7 (MMP7). Enrichment analysis and ExpiMap, a novel deep learning-based method, determined that these DEGs are involved in the Wnt signaling pathway as a primary cascade in CRC. Also, spatial transcriptome analysis showed specific expression patterns of the SFRP2 gene in fibroblast cell type. The expression of selected DEGs was confirmed on CRC and normal adjacent tissues using Real-Time quantitative PCR (RT-qPCR). Moreover, we examined the effects of postbiotics extracted from Lactobacillus acidophilus (L. acidophilus) on the proliferation, migration, and cell cycle distribution of HT-29 cells using MTT, scratch, and flow cytometry assays. Our results showed that L. acidophilus postbiotics induce cell cycle arrest at G1 phase and also had anti-proliferative and anti-migration effects on HT-29 cells, while it did not exert anti-proliferative activity on control fibroblasts. Finally, we revealed that treating HT-29 cells with postbiotics can affect the expression of selected DEGs. We suggested that L. acidophilus postbiotics have therapeutic potential in CRC by modulating key genes in the Wnt pathway.
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Affiliation(s)
- Nafiseh Erfanian
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Nasseri
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Adib Miraki Feriz
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Hossein Safarpour
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
| | - Mohammad Hassan Namaei
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran.
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Li H, Chen Z, Chen N, Fan Y, Xu Y, Xu X. Applications of lung cancer organoids in precision medicine: from bench to bedside. Cell Commun Signal 2023; 21:350. [PMID: 38057851 PMCID: PMC10698950 DOI: 10.1186/s12964-023-01332-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 09/25/2023] [Indexed: 12/08/2023] Open
Abstract
As the leading cause of cancer-related mortality, lung cancer continues to pose a menacing threat to human health worldwide. Lung cancer treatment options primarily rely on chemoradiotherapy, surgery, targeted therapy, or immunotherapy. Despite significant progress in research and treatment, the 5-year survival rate for lung cancer patients is only 10-20%. There is an urgent need to develop more reliable preclinical models and valid therapeutic approaches. Patient-derived organoids with highly reduced tumour heterogeneity have emerged as a promising model for high-throughput drug screening to guide treatment of lung cancer patients. Organoid technology offers a novel platform for disease modelling, biobanking and drug development. The expected benefit of organoids is for cancer patients as the subsequent precision medicine technology. Over the past few years, numerous basic and clinical studies have been conducted on lung cancer organoids, highlighting the significant contributions of this technique. This review comprehensively examines the current state-of-the-art technologies and applications relevant to the formation of lung cancer organoids, as well as the potential of organoids in precision medicine and drug testing. Video Abstract.
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Affiliation(s)
- Huihui Li
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
- Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Zexin Chen
- Guangdong Research Center of Organoid Engineering and Technology, Guangzhou, 510535, Guangdong, China
| | - Ning Chen
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
- Department of Oncology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yun Fan
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
- Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Yaping Xu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
| | - Xiaoling Xu
- Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
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Xu H, Jia Z, Liu F, Li J, Huang Y, Jiang Y, Pu P, Shang T, Tang P, Zhou Y, Yang Y, Su J, Liu J. Biomarkers and experimental models for cancer immunology investigation. MedComm (Beijing) 2023; 4:e437. [PMID: 38045830 PMCID: PMC10693314 DOI: 10.1002/mco2.437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 11/01/2023] [Accepted: 11/10/2023] [Indexed: 12/05/2023] Open
Abstract
The rapid advancement of tumor immunotherapies poses challenges for the tools used in cancer immunology research, highlighting the need for highly effective biomarkers and reproducible experimental models. Current immunotherapy biomarkers encompass surface protein markers such as PD-L1, genetic features such as microsatellite instability, tumor-infiltrating lymphocytes, and biomarkers in liquid biopsy such as circulating tumor DNAs. Experimental models, ranging from 3D in vitro cultures (spheroids, submerged models, air-liquid interface models, organ-on-a-chips) to advanced 3D bioprinting techniques, have emerged as valuable platforms for cancer immunology investigations and immunotherapy biomarker research. By preserving native immune components or coculturing with exogenous immune cells, these models replicate the tumor microenvironment in vitro. Animal models like syngeneic models, genetically engineered models, and patient-derived xenografts provide opportunities to study in vivo tumor-immune interactions. Humanized animal models further enable the simulation of the human-specific tumor microenvironment. Here, we provide a comprehensive overview of the advantages, limitations, and prospects of different biomarkers and experimental models, specifically focusing on the role of biomarkers in predicting immunotherapy outcomes and the ability of experimental models to replicate the tumor microenvironment. By integrating cutting-edge biomarkers and experimental models, this review serves as a valuable resource for accessing the forefront of cancer immunology investigation.
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Affiliation(s)
- Hengyi Xu
- State Key Laboratory of Molecular OncologyNational Cancer Center /National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ziqi Jia
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Fengshuo Liu
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jiayi Li
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yansong Huang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yiwen Jiang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Pengming Pu
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Tongxuan Shang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Pengrui Tang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yongxin Zhou
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yufan Yang
- School of MedicineTsinghua UniversityBeijingChina
| | - Jianzhong Su
- Oujiang LaboratoryZhejiang Lab for Regenerative Medicine, Vision, and Brain HealthWenzhouZhejiangChina
| | - Jiaqi Liu
- State Key Laboratory of Molecular OncologyNational Cancer Center /National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Landon‐Brace N, Li NT, McGuigan AP. Exploring New Dimensions of Tumor Heterogeneity: The Application of Single Cell Analysis to Organoid-Based 3D In Vitro Models. Adv Healthc Mater 2023; 12:e2300903. [PMID: 37589373 PMCID: PMC11468421 DOI: 10.1002/adhm.202300903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/28/2023] [Indexed: 08/18/2023]
Abstract
Modeling the heterogeneity of the tumor microenvironment (TME) in vitro is essential to investigating fundamental cancer biology and developing novel treatment strategies that holistically address the factors affecting tumor progression and therapeutic response. Thus, the development of new tools for both in vitro modeling, such as patient-derived organoids (PDOs) and complex 3D in vitro models, and single cell omics analysis, such as single-cell RNA-sequencing, represents a new frontier for investigating tumor heterogeneity. Specifically, the integration of PDO-based 3D in vitro models and single cell analysis offers a unique opportunity to explore the intersecting effects of interpatient, microenvironmental, and tumor cell heterogeneity on cell phenotypes in the TME. In this review, the current use of PDOs in complex 3D in vitro models of the TME is discussed and the emerging directions in the development of these models are highlighted. Next, work that has successfully applied single cell analysis to PDO-based models is examined and important experimental considerations are identified for this approach. Finally, open questions are highlighted that may be amenable to exploration using the integration of PDO-based models and single cell analysis. Ultimately, such investigations may facilitate the identification of novel therapeutic targets for cancer that address the significant influence of tumor-TME interactions.
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Affiliation(s)
- Natalie Landon‐Brace
- Institute of Biomedical EngineeringUniversity of Toronto200 College StreetTorontoM5S3E5Canada
| | - Nancy T. Li
- Department of Chemical Engineering and Applied ChemistryUniversity of Toronto200 College StTorontoM5S3E5Canada
| | - Alison P. McGuigan
- Department of Chemical Engineering and Applied ChemistryInstitute of Biomedical EngineeringUniversity of Toronto200 College StTorontoM5S3E5Canada
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Yang C, Xiao W, Wang R, Hu Y, Yi K, Sun X, Wang G, Xu X. Tumor organoid model of colorectal cancer (Review). Oncol Lett 2023; 26:328. [PMID: 37415635 PMCID: PMC10320425 DOI: 10.3892/ol.2023.13914] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/01/2023] [Indexed: 07/08/2023] Open
Abstract
The establishment of self-organizing 'mini-gut' organoid models has brought about a significant breakthrough in biomedical research. Patient-derived tumor organoids have emerged as valuable tools for preclinical studies, offering the retention of genetic and phenotypic characteristics of the original tumor. These organoids have applications in various research areas, including in vitro modelling, drug discovery and personalized medicine. The present review provided an overview of intestinal organoids, focusing on their unique characteristics and current understanding. The progress made in colorectal cancer (CRC) organoid models was then delved into, discussing their role in drug development and personalized medicine. For instance, it has been indicated that patient-derived tumor organoids are able to predict response to irinotecan-based neoadjuvant chemoradiotherapy. Furthermore, the limitations and challenges associated with current CRC organoid models were addressed, along with proposed strategies for enhancing their utility in future basic and translational research.
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Affiliation(s)
- Chi Yang
- Department of Gastroenterology, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Wangwen Xiao
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Rui Wang
- School of Pharmacy, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yan Hu
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Ke Yi
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Xuan Sun
- Department of Gastroenterology, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Guanghui Wang
- School of Pharmacy, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Xiaohui Xu
- Department of Gastroenterology, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
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Pickles OJ, Wanigasooriya K, Ptasinska A, Patel AJ, Robbins HL, Bryer C, Whalley CM, Tee L, Lal N, Pinna CM, Elzefzafy N, Taniere P, Beggs AD, Middleton GM. MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids. CANCER RESEARCH COMMUNICATIONS 2023; 3:1501-1513. [PMID: 37565053 PMCID: PMC10411481 DOI: 10.1158/2767-9764.crc-23-0091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/17/2023] [Accepted: 07/05/2023] [Indexed: 08/12/2023]
Abstract
Tumor-specific MHC class II (tsMHC-II) expression impacts tumor microenvironmental immunity. tsMHC-II positive cancer cells may act as surrogate antigen-presenting cells and targets for CD4+ T cell-mediated lysis. In colorectal cancer, tsMHC-II negativity is common, in cell lines due to CIITA promoter methylation. To clarify mechanisms of tsMHC-II repression in colorectal cancer, we analyzed colorectal cancer organoids which are epigenetically faithful to tissue of origin. 15 primary colorectal cancer organoids were treated with IFNγ ± epigenetic modifiers: flow cytometry was used for tsMHC-II expression. qRT-PCR, total RNA sequencing, nanopore sequencing, bisulfite conversion/pyrosequencing, and Western blotting was used to quantitate CIITA, STAT1, IRF1, and JAK1 expression, mutations and promoter methylation and chromatin immunoprecipitation to quantitate H3K9ac, H3K9Me2, and EZH2 occupancy at CIITA. We define three types of response to IFNγ in colorectal cancer: strong, weak, and noninducibility. Delayed and restricted expression even with prolonged IFNγ exposure was due to IFNγ-mediated EZH2 occupancy at CIITA. tsMHC-II expression was enhanced by EZH2 and histone deacetylase inhibition in the weakly inducible organoids. Noninducibility is seen in three consensus molecular subtype 1 (CMS1) organoids due to JAK1 mutation. No organoid demonstrates CIITA promoter methylation. Providing IFNγ signaling is intact, most colorectal cancer organoids are class II inducible. Upregulation of tsMHC-II through targeted epigenetic therapy is seen in one of fifteen organoids. Our approach can serve as a blueprint for investigating the heterogeneity of specific epigenetic mechanisms of immune suppression across individual patients in other cancers and how these might be targeted to inform the conduct of future trials of epigenetic therapies as immune adjuvants more strategically in cancer. Significance Cancer cell expression of MHC class II significantly impacts tumor microenvironmental immunity. Previous studies investigating mechanisms of repression of IFNγ-inducible class II expression using cell lines demonstrate epigenetic silencing of IFN pathway genes as a frequent immune evasion strategy. Unlike cell lines, patient-derived organoids maintain epigenetic fidelity to tissue of origin. In the first such study, we analyze patterns, dynamics, and epigenetic control of IFNγ-induced class II expression in a series of colorectal cancer organoids.
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Affiliation(s)
- Oliver J. Pickles
- Institute of Immunology and Immunotherapy, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Kasun Wanigasooriya
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Anetta Ptasinska
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Akshay J. Patel
- Institute of Immunology and Immunotherapy, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Helen L. Robbins
- Institute of Immunology and Immunotherapy, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Claire Bryer
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Celina M. Whalley
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Louise Tee
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Neeraj Lal
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Claudia M.A. Pinna
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Nahla Elzefzafy
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
- Cancer Biology Department, NCI, Cairo University, Cairo, Egypt
| | - Philippe Taniere
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Andrew D. Beggs
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Gary M. Middleton
- Institute of Immunology and Immunotherapy, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, United Kingdom
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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Cioce M, Fumagalli MR, Donzelli S, Goeman F, Canu V, Rutigliano D, Orlandi G, Sacconi A, Pulito C, Palcau AC, Fanciulli M, Morrone A, Diodoro MG, Caricato M, Crescenzi A, Verri M, Fazio VM, Zapperi S, Levrero M, Strano S, Grazi GL, La Porta C, Blandino G. Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids. J Exp Clin Cancer Res 2023; 42:170. [PMID: 37460938 DOI: 10.1186/s13046-023-02754-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 07/07/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Approximately 20-50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need. METHODS RNA sequencing of primary colorectal cancer specimens vs adjacent liver tissue vs synchronous and asynchronous liver metastases. Pathways enrichment analyses. The Library of Integrated Network-based Cellular Signatures (LINCS)-based and Connectivity Map (CMAP)-mediated identification of FDA-approved compounds capable to interfere with a 22 gene signature from primary CRC and liver metastases. Testing the identified compounds on CRC-Patient Derived Organoid (PDO) cultures. Microscopy and Fluorescence Activated Cell Sorting (FACS) based analysis of the treated PDOs. RESULTS We have found that liver metastases acquire features of the adjacent liver tissue while partially losing those of the primary tumors they derived from. We have identified a 22-gene signature differentially expressed among primary tumors and metastases and validated in public databases. A pharmacogenomic screening for FDA-approved compounds capable of interfering with this signature has been performed. We have validated some of the identified representative compounds in CRC-Patient Derived Organoid cultures (PDOs) and found that pentoxyfilline and, to a minor extent, dexketoprofen and desloratadine, can variably interfere with number, size and viability of the CRC -PDOs in a patient-specific way. We explored the pentoxifylline mechanism of action and found that pentoxifylline treatment attenuated the 5-FU elicited increase of ALDHhigh cells by attenuating the IL-6 mediated STAT3 (tyr705) phosphorylation. CONCLUSIONS Pentoxifylline synergizes with 5-Fluorouracil (5-FU) in attenuating organoid formation. It does so by interfering with an IL-6-STAT3 axis leading to the emergence of chemoresistant ALDHhigh cell subpopulations in 5-FU treated PDOs. A larger cohort of CRC-PDOs will be required to validate and expand on the findings of this proof-of-concept study.
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Affiliation(s)
- Mario Cioce
- Department of Medicine, Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Rome, Italy.
- Institute of Translational Pharmacology, National Research Council of Italy (CNR), Rome, Italy.
| | - Maria Rita Fumagalli
- Center for Complexity and Biosystems, Department of Environmental Science and Policy, University of Milan, Via Celoria 26, 20133, Milano, Italy
- CNR - Consiglio Nazionale Delle Ricerche, Biophysics Institute, Via De Marini 6, 16149, Genoa, Italy
| | - Sara Donzelli
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Frauke Goeman
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Valeria Canu
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Daniela Rutigliano
- Department of Medicine, Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Rome, Italy
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Giulia Orlandi
- Scientific Direction, IRCCS San Gallicano Dermatological Institute, Rome, Italy
| | - Andrea Sacconi
- Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Claudio Pulito
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Alina Catalina Palcau
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Maurizio Fanciulli
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Aldo Morrone
- Scientific Direction, IRCCS San Gallicano Dermatological Institute, Rome, Italy
| | - Maria Grazia Diodoro
- Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marco Caricato
- Colorectal Surgery Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Università Campus Bio-Medico, Rome, Italy
| | - Anna Crescenzi
- Department of Medicine, Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Rome, Italy
- Unit of Endocrine Organs and Neuromuscular Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Martina Verri
- Unit of Endocrine Organs and Neuromuscular Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Vito Michele Fazio
- Department of Medicine, Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Rome, Italy
- Institute of Translational Pharmacology, National Research Council of Italy (CNR), Rome, Italy
| | - Stefano Zapperi
- Center for Complexity and Biosystems, Department of Physics, University of Milan, Via Celoria 16, 20133, Milano, Italy
- Istituto Di Chimica Della Materia Condensata E Di Tecnologie Per L'Energia, CNR - Consiglio Nazionale Delle Ricerche, Via R. Cozzi 53, 20125, Milano, Italy
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), UMR Inserm, CNRS 5286 Mixte CLB, Université de Lyon, 1 (UCBL1), 69003, Lyon, France
| | - Sabrina Strano
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Gian Luca Grazi
- Department of Experimental and Clinical Medicine, Hepato-Biliary Pancreatic Surgery, University of Florence, Florence, Italy
| | - Caterina La Porta
- Center for Complexity and Biosystems, Department of Environmental Science and Policy, University of Milan, Via Celoria 26, 20133, Milano, Italy
- CNR - Consiglio Nazionale Delle Ricerche, Istituto Di Biofisica, Via Celoria 26, 20133, Milano, Italy
| | - Giovanni Blandino
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
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Lin H, Wang Y, Cheng C, Qian Y, Hao J, Zhang Z, Sheng W, Song L, Deng CX, Zhao B, Cao J, Wang L, Wang L, Liang L, Chen WK, Yu C, Sun Z, Yang Y, Wang C, Zhang Y, Li Q, Li K, Ma A, Zhao T, Chen YG, Hua G. Standard: Human intestinal cancer organoids. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:24. [PMID: 37378693 DOI: 10.1186/s13619-023-00167-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
Intestinal cancer is one of the most frequent and lethal types of cancer. Modeling intestinal cancer using organoids has emerged in the last decade. Human intestinal cancer organoids are physiologically relevant in vitro models, which provides an unprecedented opportunity for fundamental and applied research in colorectal cancer. "Human intestinal cancer organoids" is the first set of guidelines on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods for human intestinal cancer organoids, which apply to the production and quality control during the process of manufacturing and testing of human intestinal cancer organoids. It was released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practocal protocols, and accelerate the international standardization of human intestinal cancer organoids for clinical development and therapeutic applications.
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Affiliation(s)
- Hanqing Lin
- D1Med Technology (Shanghai) Inc, Shanghai, 201802, China
| | - Yalong Wang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
- Guangzhou Laboratory, Guangzhou, 510005, China
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Guangzhou Hua Yi Regeneration Technology Co., Ltd, Huangpu District, Guangzhou, 510700, China
| | - Chunyan Cheng
- D1Med Technology (Shanghai) Inc, Shanghai, 201802, China
| | - Yuxin Qian
- D1Med Technology (Shanghai) Inc, Shanghai, 201802, China
| | - Jie Hao
- National Stem Cell Resource Center, State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Zhen Zhang
- Department of Radiation Oncology and Cancer Institute, Fudan University Shanghai Cancer Center Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Weiqi Sheng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Linhong Song
- Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Chu-Xia Deng
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, 999078, SAR, China
| | - Bing Zhao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Jiani Cao
- National Stem Cell Resource Center, State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Lei Wang
- National Stem Cell Resource Center, State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Liu Wang
- National Stem Cell Resource Center, State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Lingmin Liang
- National Stem Cell Resource Center, State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Wenli Kelly Chen
- China Innovation Center of Roche, Li Shi Zhen Road, Pudong, Shanghai, 201203, China
| | - Chunping Yu
- Eli Lilly and Company, Pudong, Shanghai, 201203, China
| | - Zhijian Sun
- K2 Oncology Co., Ltd, KeChuang Street, Beijing, 100176, China
| | | | - Changlin Wang
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
- China National Institute of Standardization, Beijing, 100191, China
| | - Yong Zhang
- Chinese Society for Stem Cell Research, Shanghai, 200032, China
- HHLIFE Co., Inc, Shenzhen, 518040, China
| | - Qiyuan Li
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
- China National GeneBank, Shenzhen, 518000, China
| | - Ka Li
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
- Chinese Society for Stem Cell Research, Shanghai, 200032, China
| | - Aijin Ma
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
- Beijing Technology and Business University, Beijing, 100048, China.
| | - Tongbiao Zhao
- National Stem Cell Resource Center, State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Guangzhou Laboratory, Guangzhou, 510005, China.
- School of Basic Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
| | - Guoqiang Hua
- D1Med Technology (Shanghai) Inc, Shanghai, 201802, China.
- Department of Radiation Oncology and Cancer Institute, Fudan University Shanghai Cancer Center Fudan University, Shanghai, 200032, China.
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Roohani S, Loskutov J, Heufelder J, Ehret F, Wedeken L, Regenbrecht M, Sauer R, Zips D, Denker A, Joussen AM, Regenbrecht CRA, Kaul D. Photon and Proton irradiation in Patient-derived, Three-Dimensional Soft Tissue Sarcoma Models. BMC Cancer 2023; 23:577. [PMID: 37349697 DOI: 10.1186/s12885-023-11013-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 05/25/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND Despite their heterogeneity, the current standard preoperative radiotherapy regimen for localized high-grade soft tissue sarcoma (STS) follows a one fits all approach for all STS subtypes. Sarcoma patient-derived three-dimensional cell culture models represent an innovative tool to overcome challenges in clinical research enabling reproducible subtype-specific research on STS. In this pilot study, we present our methodology and preliminary results using STS patient-derived 3D cell cultures that were exposed to different doses of photon and proton radiation. Our aim was: (i) to establish a reproducible method for irradiation of STS patient-derived 3D cell cultures and (ii) to explore the differences in tumor cell viability of two different STS subtypes exposed to increasing doses of photon and proton radiation at different time points. METHODS Two patient-derived cell cultures of untreated localized high-grade STS (an undifferentiated pleomorphic sarcoma (UPS) and a pleomorphic liposarcoma (PLS)) were exposed to a single fraction of photon or proton irradiation using doses of 0 Gy (sham irradiation), 2 Gy, 4 Gy, 8 Gy and 16 Gy. Cell viability was measured and compared to sham irradiation at two different time points (four and eight days after irradiation). RESULTS The proportion of viable tumor cells four days after photon irradiation for UPS vs. PLS were significantly different with 85% vs. 65% (4 Gy), 80% vs. 50% (8 Gy) and 70% vs. 35% (16 Gy). Proton irradiation led to similar diverging viability curves between UPS vs. PLS four days after irradiation with 90% vs. 75% (4 Gy), 85% vs. 45% (8 Gy) and 80% vs. 35% (16 Gy). Photon and proton radiation displayed only minor differences in cell-killing properties within each cell culture (UPS and PLS). The cell-killing effect of radiation sustained at eight days after irradiation in both cell cultures. CONCLUSIONS Pronounced differences in radiosensitivity are evident among UPS and PLS 3D patient-derived sarcoma cell cultures which may reflect the clinical heterogeneity. Photon and proton radiation showed similar dose-dependent cell-killing effectiveness in both 3D cell cultures. Patient-derived 3D STS cell cultures may represent a valuable tool to enable translational studies towards individualized subtype-specific radiotherapy in patients with STS.
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Affiliation(s)
- Siyer Roohani
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353, Berlin, Germany.
- Charité - Universitätsmedizin Berlin, German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), 69120, Berlin, Heidelberg, Germany.
| | - Jürgen Loskutov
- CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Jens Heufelder
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, BerlinProtonen am Helmholtz-Zentrum Berlin, 14109, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Ophthalmology, 12200, Berlin, Germany
| | - Felix Ehret
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353, Berlin, Germany
- Charité - Universitätsmedizin Berlin, German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), 69120, Berlin, Heidelberg, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Lena Wedeken
- CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Manuela Regenbrecht
- CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
- Helios Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125, Berlin, Germany
- ASC Oncology GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Rica Sauer
- Institute of Pathology, Helios Klinikum Emil von Behring, Walterhöferstr. 11, 14165, Berlin, Germany
| | - Daniel Zips
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353, Berlin, Germany
- Charité - Universitätsmedizin Berlin, German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), 69120, Berlin, Heidelberg, Germany
| | - Andrea Denker
- Helmholtz-Zentrum Berlin für Materialien und Energie, 14109, Berlin, Germany
| | - Antonia M Joussen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Ophthalmology, 12200, Berlin, Germany
| | - Christian R A Regenbrecht
- CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
- ASC Oncology GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
- Institut für Pathologie, Universitätsmedizin Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Germany
| | - David Kaul
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353, Berlin, Germany
- Charité - Universitätsmedizin Berlin, German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), 69120, Berlin, Heidelberg, Germany
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Wang Y, Lin H, Zhao L, Hong F, Hao J, Zhang Z, Sheng W, Song L, Deng CX, Zhao B, Cao J, Wang L, Wang L, Liang L, Chen WK, Yu C, Sun Z, Yang Y, Wang C, Zhang Y, Li Q, Li K, Ma A, Zhao T, Hua G, Chen YG. Standard: Human intestinal organoids. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:23. [PMID: 37314549 DOI: 10.1186/s13619-023-00168-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Organoids have attracted great interest for disease modelling, drug discovery and development, and tissue growth and homeostasis investigations. However, lack of standards for quality control has become a prominent obstacle to limit their translation into clinic and other applications. "Human intestinal organoids" is the first guideline on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods, inspection rules for human intestinal organoids, which is applicable to quality control during the process of manufacturing and testing of human intestinal organoids. It was originally released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of human intestinal organoids for applications.
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Affiliation(s)
- Yalong Wang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
- Guangzhou Laboratory, Guangzhou, 510005, China
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Guangzhou Hua Yi Regeneration Technology Co., Ltd, Huangpu District, Guangzhou, 510700, China
| | - Hanqing Lin
- D1Med Technology (Shanghai) Inc, Shanghai, 201802, China
| | - Lianzheng Zhao
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Fan Hong
- Guangzhou Laboratory, Guangzhou, 510005, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Zhen Zhang
- Department of Radiation Oncology and Cancer Institute, Fudan University Shanghai Cancer Center Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Weiqi Sheng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Linhong Song
- Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Chu-Xia Deng
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, 999078, SAR, China
| | - Bing Zhao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Jiani Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Lei Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Liu Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Lingmin Liang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Wenli Kelly Chen
- China Innovation Center of Roche, Li Shi Zhen Road, Pudong, Shanghai, 201203, China
| | - Chunping Yu
- Eli Lilly and Company, Pudong, Shanghai, 201203, China
| | - Zhijian Sun
- K2 Oncology Co., Ltd, KeChuang Street, Beijing, 100176, China
| | | | - Changlin Wang
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
- China National Institute of Standardization, Beijing, 100191, China
| | - Yong Zhang
- Chinese Society for Stem Cell Research, Shanghai, 200032, China
- HHLIFE Co., Inc, Shenzhen, 518040, China
| | - Qiyuan Li
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
- China National GeneBank, Shenzhen, 518000, China
| | - Ka Li
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
- Chinese Society for Stem Cell Research, Shanghai, 200032, China
| | - Aijin Ma
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
- Beijing Technology and Business University, Beijing, 100048, China.
| | - Tongbiao Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
| | - Guoqiang Hua
- D1Med Technology (Shanghai) Inc, Shanghai, 201802, China.
- Department of Radiation Oncology and Cancer Institute, Fudan University Shanghai Cancer Center Fudan University, Shanghai, 200032, China.
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Guangzhou Laboratory, Guangzhou, 510005, China.
- School of Basic Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
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Morelli M, Kurek D, Ng CP, Queiroz K. Gut-on-a-Chip Models: Current and Future Perspectives for Host-Microbial Interactions Research. Biomedicines 2023; 11:biomedicines11020619. [PMID: 36831155 PMCID: PMC9953162 DOI: 10.3390/biomedicines11020619] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
The intestine contains the largest microbial community in the human body, the gut microbiome. Increasing evidence suggests that it plays a crucial role in maintaining overall health. However, while many studies have found a correlation between certain diseases and changes in the microbiome, the impact of different microbial compositions on the gut and the mechanisms by which they contribute to disease are not well understood. Traditional pre-clinical models, such as cell culture or animal models, are limited in their ability to mimic the complexity of human physiology. New mechanistic models, such as organ-on-a-chip, are being developed to address this issue. These models provide a more accurate representation of human physiology and could help bridge the gap between clinical and pre-clinical studies. Gut-on-chip models allow researchers to better understand the underlying mechanisms of disease and the effect of different microbial compositions on the gut. They can help to move the field from correlation to causation and accelerate the development of new treatments for diseases associated with changes in the gut microbiome. This review will discuss current and future perspectives of gut-on-chip models to study host-microbial interactions.
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Yang W, Li Y, Shi F, Liu H. Human lung organoid: Models for respiratory biology and diseases. Dev Biol 2023; 494:26-34. [PMID: 36470449 DOI: 10.1016/j.ydbio.2022.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/23/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
The human respiratory system, consisting of the airway and alveoli, is one of the most complex organs directly interfaced with the external environment. The diverse epithelial cells lining the surface are usually the first cell barrier that comes into contact with pathogens that could lead to deadly pulmonary disease. There is an urgent need to understand the mechanisms of self-renewal and protection of these epithelial cells against harmful pathogens, such as SARS-CoV-2. Traditional models, including cell lines and mouse models, have extremely limited native phenotypic features. Therefore, in recent years, to mimic the complexity of the lung, airway and alveoli organoid technology has been developed and widely applied. TGF-β/BMP/SMAD, FGF and Wnt/β-catenin signaling have been proven to play a key role in lung organoid expansion and differentiation. Thus, we summarize the current novel lung organoid culture strategies and discuss their application for understanding the lung biological features and pathophysiology of pulmonary diseases, especially COVID-19. Lung organoids provide an excellent in vitro model and research platform.
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Affiliation(s)
- Wenhao Yang
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan University, Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology Sichuan University, Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yingna Li
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan University, Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology Sichuan University, Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Fang Shi
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan University, Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology Sichuan University, Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan University, Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology Sichuan University, Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
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The Efficacy of Using Patient-Derived Organoids to Predict Treatment Response in Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15030805. [PMID: 36765763 PMCID: PMC9913532 DOI: 10.3390/cancers15030805] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/24/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer is an important cause of morbidity and mortality worldwide. The current treatment landscape includes chemotherapy, targeted therapy, immunotherapy, radiotherapy, and surgery. A key challenge to improving patient outcomes is the significant inter-patient heterogeneity in treatment response. Tumour organoids derived from the patients' tumours via surgically resected or endoscopically biopsied tissue, have emerged as promising models for personalised medicine. This review synthesises the findings, to date, of studies which have explored the efficacy of ex vivo organoid sensitivity testing for predicting treatment response. Most studies have focused on predicting the response to standard-of-care radiotherapy and chemotherapy options. There is strong evidence to support organoid sensitivity testing of ionising radiation, 5-fluorouracil, and irinotecan, and to a lesser extent, oxaliplatin and TAS-102. Fewer studies have used organoids to identify patients who are likely to benefit from novel treatment options that otherwise remain in clinical trials. This review also summarises recent advancements in organoid culture to include non-epithelial components of the tumour microenvironment, to allow testing of immunotherapy and certain targeted therapy options. Overall, further prospective trials will support the implementation of organoid-based personalised medicine for colorectal cancer patients in the future.
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Huang X, Han C, Zhong J, Hu J, Jin Y, Zhang Q, Luo W, Liu R, Ling F. Low expression of the dynamic network markers FOS/JUN in pre-deteriorated epithelial cells is associated with the progression of colorectal adenoma to carcinoma. J Transl Med 2023; 21:45. [PMID: 36698183 PMCID: PMC9875500 DOI: 10.1186/s12967-023-03890-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Deterioration of normal intestinal epithelial cells is crucial for colorectal tumorigenesis. However, the process of epithelial cell deterioration and molecular networks that contribute to this process remain unclear. METHODS Single-cell data and clinical information were downloaded from the Gene Expression Omnibus (GEO) database. We used the recently proposed dynamic network biomarker (DNB) method to identify the critical stage of epithelial cell deterioration. Data analysis and visualization were performed using R and Cytoscape software. In addition, Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis was used to identify potential transcription factors, and CellChat analysis was conducted to evaluate possible interactions among cell populations. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analysis (GSVA) analyses were also performed. RESULTS The trajectory of epithelial cell deterioration in adenoma to carcinoma progression was delineated, and the subpopulation of pre-deteriorated epithelial cells during colorectal cancer (CRC) initialization was identified at the single-cell level. Additionally, FOS/JUN were identified as biomarkers for pre-deteriorated epithelial cell subpopulations in CRC. Notably, FOS/JUN triggered low expression of P53-regulated downstream pro-apoptotic genes and high expression of anti-apoptotic genes through suppression of P53 expression, which in turn inhibited P53-induced apoptosis. Furthermore, malignant epithelial cells contributed to the progression of pre-deteriorated epithelial cells through the GDF signaling pathway. CONCLUSIONS We demonstrated the trajectory of epithelial cell deterioration and used DNB to characterize pre-deteriorated epithelial cells at the single-cell level. The expression of DNB-neighboring genes and cellular communication were triggered by DNB genes, which may be involved in epithelial cell deterioration. The DNB genes FOS/JUN provide new insights into early intervention in CRC.
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Affiliation(s)
- Xiaoqi Huang
- grid.79703.3a0000 0004 1764 3838Guangdong Key Laboratory of Fermentation and Enzyme Engineering, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006 China
| | - Chongyin Han
- grid.79703.3a0000 0004 1764 3838Guangdong Key Laboratory of Fermentation and Enzyme Engineering, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006 China
| | - Jiayuan Zhong
- grid.79703.3a0000 0004 1764 3838School of Mathematics, South China University of Technology, Guangzhou, 510641 China
| | - Jiaqi Hu
- grid.79703.3a0000 0004 1764 3838Guangdong Key Laboratory of Fermentation and Enzyme Engineering, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006 China
| | - Yabin Jin
- grid.452881.20000 0004 0604 5998Institute of Clinical Research, The First People’s Hospital of Foshan, Foshan, 528000 China
| | - Qinqin Zhang
- grid.79703.3a0000 0004 1764 3838Guangdong Key Laboratory of Fermentation and Enzyme Engineering, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006 China
| | - Wei Luo
- grid.452881.20000 0004 0604 5998Institute of Clinical Research, The First People’s Hospital of Foshan, Foshan, 528000 China
| | - Rui Liu
- grid.79703.3a0000 0004 1764 3838School of Mathematics, South China University of Technology, Guangzhou, 510641 China ,grid.513189.7Pazhou Lab, Guangzhou, 510330 China
| | - Fei Ling
- grid.79703.3a0000 0004 1764 3838Guangdong Key Laboratory of Fermentation and Enzyme Engineering, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006 China
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Harada K, Sakamoto N. Cancer organoid applications to investigate chemotherapy resistance. Front Mol Biosci 2022; 9:1067207. [PMID: 36582205 PMCID: PMC9792487 DOI: 10.3389/fmolb.2022.1067207] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/30/2022] [Indexed: 12/15/2022] Open
Abstract
In clinical practice, a large proportion of cancer patients receive chemotherapy, yet tumors persist or acquire resistance; removing this obstacle could help to lower the number of cancer-related fatalities. All areas of cancer research are increasingly using organoid technology, a culture technique that simulates the in vivo environment in vitro, especially in the quickly developing fields of anticancer drug resistance, drug-tolerant persisters, and drug screening. This review provides an overview of organoid technology, the use of organoids in the field of anticancer drug resistance research, their relevance to clinical information and clinical trials, and approaches to automation and high throughput.
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Affiliation(s)
- Kenji Harada
- Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan,Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Naoya Sakamoto
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan,*Correspondence: Naoya Sakamoto,
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Su M, Pan T, Chen QZ, Zhou WW, Gong Y, Xu G, Yan HY, Li S, Shi QZ, Zhang Y, He X, Jiang CJ, Fan SC, Li X, Cairns MJ, Wang X, Li YS. Data analysis guidelines for single-cell RNA-seq in biomedical studies and clinical applications. Mil Med Res 2022; 9:68. [PMID: 36461064 PMCID: PMC9716519 DOI: 10.1186/s40779-022-00434-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/18/2022] [Indexed: 12/03/2022] Open
Abstract
The application of single-cell RNA sequencing (scRNA-seq) in biomedical research has advanced our understanding of the pathogenesis of disease and provided valuable insights into new diagnostic and therapeutic strategies. With the expansion of capacity for high-throughput scRNA-seq, including clinical samples, the analysis of these huge volumes of data has become a daunting prospect for researchers entering this field. Here, we review the workflow for typical scRNA-seq data analysis, covering raw data processing and quality control, basic data analysis applicable for almost all scRNA-seq data sets, and advanced data analysis that should be tailored to specific scientific questions. While summarizing the current methods for each analysis step, we also provide an online repository of software and wrapped-up scripts to support the implementation. Recommendations and caveats are pointed out for some specific analysis tasks and approaches. We hope this resource will be helpful to researchers engaging with scRNA-seq, in particular for emerging clinical applications.
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Affiliation(s)
- Min Su
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166 China
| | - Tao Pan
- College of Biomedical Information and Engineering, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, 571199 Hainan China
| | - Qiu-Zhen Chen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166 China
| | - Wei-Wei Zhou
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081 Heilongjiang China
| | - Yi Gong
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166 China
- Department of Immunology, Nanjing Medical University, Nanjing, 211166 China
| | - Gang Xu
- College of Biomedical Information and Engineering, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, 571199 Hainan China
| | - Huan-Yu Yan
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166 China
| | - Si Li
- College of Biomedical Information and Engineering, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, 571199 Hainan China
| | - Qiao-Zhen Shi
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166 China
| | - Ya Zhang
- College of Biomedical Information and Engineering, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, 571199 Hainan China
| | - Xiao He
- Department of Laboratory Medicine, Women and Children’s Hospital of Chongqing Medical University, Chongqing, 401174 China
| | | | - Shi-Cai Fan
- Shenzhen Institute for Advanced Study, University of Electronic Science and Technology of China, Shenzhen, 518110 Guangdong China
| | - Xia Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081 Heilongjiang China
| | - Murray J. Cairns
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, the University of Newcastle, University Drive, Callaghan, NSW 2308 Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305 Australia
| | - Xi Wang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166 China
| | - Yong-Sheng Li
- College of Biomedical Information and Engineering, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, 571199 Hainan China
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Wen L, Tang F. Organoid research on human early development and beyond. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:512-523. [PMID: 37724162 PMCID: PMC10471100 DOI: 10.1515/mr-2022-0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/03/2022] [Indexed: 09/20/2023]
Abstract
The organoid field has been developing rapidly during the last decade. Organoids for human pre-, peri- and post-implantation development have opened an avenue to study these biological processes in vitro, which have been hampered by lack of accessible research models for long term. The technologies of four fields, single cell omics sequencing, genome editing and lineage tracing, microfluidics and tissue engineering, have fueled the rapid development of the organoid field. In this review, we will discuss the organoid research on human early development as well as future directions of the organoid field combining with other powerful technologies.
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Affiliation(s)
- Lu Wen
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, P. R. China
| | - Fuchou Tang
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, P. R. China
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Wang Q, Guo F, Jin Y, Ma Y. Applications of human organoids in the personalized treatment for digestive diseases. Signal Transduct Target Ther 2022; 7:336. [PMID: 36167824 PMCID: PMC9513303 DOI: 10.1038/s41392-022-01194-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/09/2022] [Accepted: 09/13/2022] [Indexed: 11/15/2022] Open
Abstract
Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.
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Affiliation(s)
- Qinying Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fanying Guo
- School of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yutao Jin
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanlei Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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