Fumagalli, A. et al. eCollection 2022 Dec. Prostate cancer patient-derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens. Nephron. Patient-derived cancer organoids have taken a prominent role in pre-clinical and translational research and have been generated for most common solid tumors. Organoids develop by self-organisation, and can accurately represent the diverse genetic, cellular and pathophysiological hallmarks of cancer. Science 358, 234238 (2017). Cancer survival rates have significantly improved following decades of cancer research. 35, 577582 (2017). Colorectal carcinoma is a highly prevalent and heterogeneous gastrointestinal malignancy. Nat. A precursor colorectal cancer (CRC) subtype that is characterized by a serrated histopathological morphology. (IELs). Liver Physiol. Rizvi, N. A. et al. volume123,pages 12091218 (2020)Cite this article. Patient derived organoids to model rare prostate cancer phenotypes. Evaluation of anticancer agents using patient-derived tumor organoids characteristically similar to source tissues. Endosc. Sakamoto, N. et al. By contrast, artificial manipulation or natural genetic mutations confer on immortalised cell lines the ability to proliferate indefinitely, making them a more convenient and well-established preclinical model, but rendering them less representative of the original tumour; furthermore, serial passages induce genotypic and phenotypic changes that might confound experimental results.11 Irrespective of their origin, 2D cell cultures cannot replicate intra-tumour cellular heterogenicity, lack the complex extracellular microenvironment, have forced apicobasal polarity and are grown as a monolayer with unnatural suspension and adherence forces. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Carcinogenesis 38, 953965 (2017). Cell 159, 176187 (2014). Replacing, reducing and refining (3Rs) the use of animals in research is an international priority, and patient-derived organoid cultures represent an exciting platform to facilitate this principle. Development 144, 11181127 (2017). Overall, this cutting-edge method continues to evolve to provide new insights into the pathogenesis and evolution of cancer, offering the opportunity to develop new treatment strategies and enhance the impact of cancer research. Long-term organoid culture is possible, with most groups reporting successful culture up to 6 months,27,33 and some groups reporting success beyond 1 year.43 Patient- and disease-specific characteristics are retained well over several passages.43 There is evidence that mutations do accumulate over time33 although this is perhaps unsurprising, given the known evolution of cancer in vivo,44,45 and this is consistent with tumour evolution in vitro.36 Tumour organoids also possess distinct organoid signatures that reflect real-life inter-patient variability.46 However, such inter-patient variability increases the sample-size requirements for robust power calculation-based experiments, which can be expensive. Genome editing in organoids has also revealed novel insights into the pathophysiology of previously hard-to-model diseases. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. Gastroenterology 141, 17621772 (2011). Cell 168, 613628 (2017). & Murray, G. I. Ch 8, 109131 (Academic Press, 2014). Sci. Matano, M. et al. Annu. Workman, M. J. et al. Sci. Correspondence to Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Individualised cancer therapy based on ex vivo experiments using a patients own cancer organoids represents an ambitious goal for personalised medicine, and this approach is currently not achievable and is too expensive for most healthcare systems. Natl Acad. Unique combinations of mutation types caused by different mutational processes. investigated the transplantation of lympho-organoids into the region of dissected lymph nodes in mice.112 The lympho-organoids became fully integrated into the endogenous lymphatic system and restored lymphatic drainage. Many laboratory findings fail to translate to the clinic because cell cultures do not accurately recapitulate cell behaviour and function within the wider tumour microenvironment, which includes the extracellular matrix, blood vessels, signalling components and other cell types. Aggarwal D, Russo S, Naik P, Bhatia S, Spector DL. Both models maintain key features from their parental tumours, such as genetic and phenotypic heterogeneity, which allows them to be used for a wide spectrum of applications. Prospective derivation of a living organoid biobank of colorectal cancer patients. 238, 137140 (2016). 6, 95119 (2011). Pancreatic cancer organoids for determining sensitivity to bromodomain and extra-terminal inhibitors (BETI). Cancer 121, 101108 (2019). van de Wetering, M. et al. Radical surgery for breast cancer is often accompanied by radiotherapy or lymph node dissection. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barretts epithelium. Protoc. Jin, K., Teng, L., Shen, Y., He, K., Xu, Z. The number and appearance of chromosomes in the nucleus of a cell. Commun. Prospective derivation of a living organoid biobank of colorectal cancer patients. Koo, B. K., van Es, J. H., van den Born, M. & Clevers, H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43; Znrf3-mutant neoplasia. Haematoxylin and eosin staining demonstrated that the organoids had pseudostratified epithelium, comprising basal cells and luminal cells that resembled normal bronchial mucosa. Additionally, organoids can be grown with high efficiency from patient-derived healthy and tumour tissues, potentially enabling patient-specific drug testing and the development of individualized treatment regimens. The authors contributed equally to the creation of this paper. The generation of cancer organoids is accomplished in a short. A multi-site metastasis-on-a-chip microphysiological system for assessing metastatic preference of cancer cells. Previously, the interval between specimen collection and successful establishment of organoid culture has been dictated by the viability of fresh samples, which has limited the time, location and demographics from which a patient sample can be taken, but Tsai et al.32 published a robust method in 2018 to cryopreserve fresh human biopsy tissue and later thaw the specimen to generate gastrointestinal organoid cultures, thus overcoming this limitation. Ther. HCMI has over 200 organoid models that are available to the research community and whose goal is to generate and annotate . Google Scholar. Nature Reviews Cancer 11, piieaay2574 (2019). Fumagalli, A., Drost, J., Suijkerbuijk, S. J., van Boxtel, R., de Ligt, J., Offerhaus, G. J. et al. Cell Host Microbe 18, 147156 (2015). Clevers H. Modeling development and disease with organoids. Kraiczy, J., Nayak, K. M., Howell, K. J., Ross, A., Forbester, J., Salvestrini, C. et al. Deaths registered in England and Wales: 2017. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsregistrationsummarytables/2017 (2018). Roper, J., Tammela, T., Cetinbas, N. M., Akkad, A., Roghanian, A., Rickelt, S. et al. Conversion of terminally committed hepatocytes to culturable bipotent progenitor cells with regenerative capacity. Commun. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. The diverse methods for tissue acquisition and the ability to cryopreserve specimens highlight the functional utility of organoid culture across a variety of cancer types and clinical situations. Basal cells as stem cells of the mouse trachea and human airway epithelium. 35, 569576 (2017). Roper, J. et al. Tamura, H., Higa, A., Hoshi, H., Hiyama, G., Takahashi, N., Ryufuku, M. et al. Nature 545, 187192 (2017). Nat. Transl. Stem cells display unique markers such as leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) in the intestine. Nat Rev Cancer 18, 407418 (2018). Please enable it to take advantage of the complete set of features! Cell 44, 533534 (2018). Before Mouse-derived gastric organoid and immune cell co-culture for the study of the tumor microenvironment. . Organoids are novel, complex, three-dimensional ex vivo tissue cultures that are derived from embryonic stem cells, induced pluripotent stem cells or tissue-resident progenitor cells, and represent a near-physiological model for studying cancer. Roerink, S. et al. 372, 25092520 (2015). Visualization and targeting of LGR5+ human colon cancer stem cells. doi: 10.3791/64889. PD-1 Blockade in tumors with mismatch-repair deficiency. Patient-derived xenografts undergo mouse-specific tumor evolution. Science 348, 124128 (2015). Organoids in cancer research Jarno Drost & Hans Clevers Nature Reviews Cancer 18 , 407-418 ( 2018) Cite this article 74k Accesses 824 Citations 184 Altmetric Metrics Abstract The recent. Therapeutic regeneration of lymphatic and immune cell functions upon lympho-organoid transplantation. Cell 159, 163175 (2014). Nat. Using organoid cultures derived from healthy tissues, different aspects of tumour initiation and progression are widely studied including the role of pathogens or specific cancer genes. Gao, M., Lin, M., Rao, M., Thompson, H., Hirai, K., Choi, M. et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. A critical player in organoid cultures is the stem cell, a self-renewing cell that can give rise to many different cell types within a tissue. Cell Mol. Eder, A., Vollert, I., Hansen, A. Rev. Sci. The critical steps involved in establishing a colonic organoid culture are a fresh colonic mucosa is obtained from human specimens (e.g., by biopsy or surgical resection), b colonic Lgr5+ stem cell-containing crypts are isolated and embedded in a basement membrane matrix, such as Matrigel and c colonic organoids are cultured in conditioned media containing specific growth factors and grow with a central lumen and representative apicobasal polarity. Federal government websites often end in .gov or .mil. Google Scholar. Gels 6, pii E10 (2020). 21, 13641371 (2015). b Transwell cell culture systems further improve the versatility of this model by allowing access to apical (luminal) and basal surfaces. This review aims to highlight how organoids are shaping the future of cancer research. Science 350, 207211 (2015). Gao, D. et al. Organoids are a promising 3D culture system between 2D cultures and in vivo models that allow the manipulation of signaling pathways and genome editing of cells in a body-like environment but lack the many disadvantages of a living system. Ireson, C. R., Alavijeh, M. S., Palmer, A. M., Fowler, E. R. & Jones, H. J. PubMedGoogle Scholar. Sci. Isolation of circulating tumor cells in an orthotopic mouse model of colorectal cancer. USA 112, 1330813311 (2015). Sci. Gastroenterology 141, 17621772 (2011). Drost, J., van Boxtel, R., Blokzijl, F., Mizutani, T., Sasaki, N., Sasselli, V. et al. Med. Curr. Cell Rep. 18, 263274 (2017). Open Access articles citing this article. Organotypic models of patient-specific tumours are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. 130, e56960 (2017). Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. "We thought," Tamura says, "this would be the best opportunity to introduce Fukushima patient-derived organoids to . EMBO Mol. There are several model systems used to study cancer in the laboratory. Patient-derived (cancer) organoids have already been used to generate 'living' organoid biobanks that can be exposed to different drugs for efficacy screenings and drug discovery validations. Roohani S, Loskutov J, Heufelder J, Ehret F, Wedeken L, Regenbrecht M, Sauer R, Zips D, Denker A, Joussen AM, Regenbrecht CRA, Kaul D. BMC Cancer. eCollection 2022. Stem cell-derived organoids and their application for medical research and patient treatment. A., Arnold, J. W., Samsa, L. A., Gaynor, L., DiSalvo, M., Cocchiaro, J. L. et al. Nat. ISSN 1532-1827 (online) Transl. The advantages and disadvantages of these models are outlined here. In addition, new methods to overcome this issue for high-throughput applications are emerging, including the use of bioprinting with alternative support matrix combinations to allow organoid culture in small-well culture plates, for example 96- or 384-well plates.94. 162, 234240 (2018). Melatonin blunted the angiogenic activity in 3D colon cancer tumoroids by the reduction of endocan. Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. A., Al-Shraideh, Y., Wang, L., Nonn, L. et al. Such examples include lentiviral transduction of prostate epithelial organoids to demonstrate that genetic alterations that are commonly found in human prostate cancer can be modelled in human organoid culture,58 and magnetic nanoparticle viral transduction of gastrointestinal organoids for further study in in vitro assays or in vivo functional analyses in mice.59. Takeda, H., Kataoka, S., Nakayama, M., Ali, M. A. E., Oshima, H., Yamamoto, D. et al. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Velletri, T., Villa, E. C., Lupia, M., Riso, P. L., Luongo, R., Tobon, A. L. et al. Furthermore, this approach could facilitate the generation of T-cell populations that could be used for autologous T-cell transfer therapy. 2022 Aug 12;12:976065. doi: 10.3389/fonc.2022.976065. Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Establishment of 2.5D organoid culture model using 3D bladder cancer organoid culture. Cancer modeling meets human organoid technology. Genet. They possess spatially restricted lineage commitment and higher-order self-assembly, which makes them attractive near-physiological models.7 This review will firstly discuss the advantages and disadvantages of the experimental model systems that are currently used in cancer research, leading to a review of tumour-derived organoid model systems, including applications in cancer research, highlighting advantages, including potential utility in personalised medicine, limitations and future perspectives. However, a bespoke, clinically relevant, drug screen could be performed on the resistant organoid culture to identify effective chemotherapy agents, and this approach appears more feasible at present. Article These organoids serve as screening tools for toxic chemicals in . Res. Sci Transl Med 8, 344ra384 (2016). Progress of research on tumor organoids: A bibliometric analysis of relevant publications from 2011 to 2021. Nature 516, 400404 (2014). Gengenbacher, N., Singhal, M. & Augustin, H. G. Preclinical mouse solid tumour models: status quo, challenges and perspectives. Patient-derived cancer models: Valuable platforms for anticancer drug testing. 35, 577582 (2017). Nature 513, 422425 (2014). Using human intestinal organoids . A large body of literature now documents patient-derived organoids (PDO) as faithfully recapitulating functional and mutational spectra of parent colon and rectal tumors in vivo ().Importantly, use of the organoid system allows for enrichment of the cancer cell . Jin MZ, Han RR, Qiu GZ, Ju XC, Lou G, Jin WL. This set-up can more accurately reflect the conditions of the tumour microenvironment in certain cancers, such as the luminal surface of colorectal cancer.75 Usui et al.75,76 successfully developed airliquid interface organoid models from normal and tumour colorectal tissues of human patients, and were able to demonstrate the presence of epithelial, goblet and fibroblast cells in normal colonic tissue, and epithelial, goblet, myofibroblast and cancer stem cells in colorectal cancer tissue, as well as to show that colorectal tumour organoids were more resistant to chemotherapeutic agents than colorectal cancer cell lines. & Jansen, M. The Barretts gland in phenotype space. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. (Humana Press, Totowa, NJ, 2011). Fessler, E. et al. Cancer mortality rates have significantly declined by ~26% over the past two decades,1 a decrease that is attributable to early diagnosis and treatment of malignancy, evidence-based clinical pathways for surveillance and management of premalignant lesions, increased awareness of health-related behaviours such as smoking and clinically focused cancer research. Clin. Cheon, D. J. Nat. Mouse models for cancer immunotherapy research. Mol. Rev. Immun. Google Scholar. Breakdown of the epithelial barrier, with the consequent translocation of bacteria and luminal antigens through the colonic mucosa, is believed to be an important initiating event in colorectal carcinogenesis,62 and a protocol for the microinjection of fluorescently labelled dextran into patient-derived human intestinal organoids establishes a platform to study epithelial barrier dynamics in vitro.61 Breakdown of the epithelial barrier will result in increased permeability and translocation of fluorescently labelled dextran from the organoid lumen to the extracellular space. Cell Stem Cell 13, 653658 (2013). Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Recent emergence of organoid technology has bridged the gap between cancer cell lines and xenografts in preclinical studies. 96, 214224 (2016). Proc. References 96 and 99 describe the use of intestinal organoids to study the contribution of CSCs to primary and metastatic CRC. Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N. et al. ORourke, K. P., Loizou, E., Livshits, G., Schatoff, E. M., Baslan, T., Manchado, E. et al. Med. Aleman, J. Chemodetection and destruction of host urea allows Helicobacter pylori to locate the epithelium. Am. Cancer Lett. You are using a browser version with limited support for CSS. Design and construction of a multi-organ microfluidic chip mimicking the in vivo microenvironment of lung cancer metastasis. Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy. Nature 488, 665669 (2012). Sci. 34, pii:e100300 (2019). Ballet, F. Hepatotoxicity in drug development: detection, significance and solutions. Cell 172, 373386.e10 (2017). H. & Orsulic, S. Mouse models of cancer. Established cultures demonstrate intra-tumour and inter-patient heterogenicity, and can be further modified by genome editing, co-culture and orthotopic transplantation into rodents. 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. Med. The authors thank K. Kretzschmar and J. Meijerink for critical reading of the manuscript. & Liu, Q. R-Spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Organoids recapitulate the structure, function, and genetic signature of the original organ, thus providing a solid foundation for future research on stem cells, regenerative biology, organogenesis, precision medicine, and human pathologies ( 2 ). Dis. Groenendijk, F. H. & Bernards, R. Drug resistance to targeted therapies: deja vu all over again. Nat. Curr. Finnberg, N. K. et al. Spheroids can be generated from immortalised cell lines, primary cells or fragments of tissue and, as such, their viability is limited as they do not contain a progenitor phenotype. Gastroenterol. For example, oesophageal adenocarcinoma organoids derived from oesophagectomy tissue specimens recapitulate the diverse genomic and transcriptomic landscape of the primary tumour,33,34 and histological assessment of these organoids demonstrated that the original tumour architecture and protein expression profile was maintained.33 This faithful representation has been reported across a variety of other tumour types, including, but not limited to, lung, ovarian, uterine, colorectal, bladder, liver, breast and biliary tract cancers.29,34,35,36,37,38 There is also evidence that epigenetic signatures in organoids appear to be reflective of those found in the primary lesion, indicating that the biology of the tumour is broadly represented.39. Huang, J. Y. et al. Commun. Nat. Smittenaar, C. R., Petersen, K. A., Stewart, K. & Moitt, N. Cancer incidence and mortality projections in the UK until 2035. Narmi MT, Shoja HM, Haiaty S, Mahdipour M, Rahbarghazi R. Cancer Cell Int. In contrast to patientderived xenografts . Nature 541, 321330 (2017). Biotechnol. Nat. Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity. Hay, M., Thomas, D. W., Craighead, J. L., Economides, C. & Rosenthal, J. 1). 6, 301319 (2018). Recreating structural morphology is especially important for cancers that arise from tissues with high structural organisation, such as the colon and rectum. Curr. A high-resolution molecular history of intra-cancer diversification. 35, 569576 (2017). Thank you for visiting nature.com. Ootani, A. et al. Gene signatures of quiescent glioblastoma cells reveal mesenchymal shift and interactions with niche microenvironment. Pathol. 46, 573582 (2014). Dekkers, J. F. et al. c Transwell experiments are effective at exploring how luminal antigens or cytokines impact epithelial barrier integrity in cancer (i.e., through movement of fluorescein isothiocyanatedextran or changes in transepithelial electrical resistance). A similar case exists in rectal cancer, for which there is a lack of anatomically relevant endoluminal rectal cancer mouse models. As an example, patient-derived tumour organoids could help determine whether a particular patient will be sensitive or resistant to specific treatments for many cancer types in a personalised medicine approach.95,96,97,98 This knowledge could be especially useful when there are a lack of robust data from large randomised control trials, which is often the case for rare and metastatic cancers. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases. J Cell Biol 2017; 216: 31-40. Med. 87, 14741480 (2018). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in The https:// ensures that you are connecting to the Generation, evolution, interfering factors, applications, and challenges of patient-derived xenograft models in immunodeficient mice. PubMed An official website of the United States government. Stronen, E. et al. 10, 106 (2017). Kessler, M. et al. 2019 Jun 7;364(6444):952-955. doi: 10.1126/science.aaw6985. A., Zamponi, M., Sullivan, S. M., Palmer, X. L. et al. These amazing three-dimensional constructs. Saito, Y., Muramatsu, T., Kanai, Y., Ojima, H., Sukeda, A., Hiraoka, N. et al. 4, 161165 (2005). Cell 144, 646674 (2011). CAS J. Hematol. Kamb, A. Whats wrong with our cancer models? Orthotopic transplantation can also take place after phenotypic and/or genotypic characterisation and/or manipulation of the tumour. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. eLife 5, pii: e18489 (2016). Internet Explorer). Google Scholar. PubMed Co-cultures are not a new concept in the laboratory, as they are often used to study interactions between epithelial cells and other important cell populations, such as lymphocytes, neurones and blood vessels. 21 June 2023, Access Nature and 54 other Nature Portfolio journals, Get Nature+, our best-value online-access subscription, Receive 12 print issues and online access, Prices may be subject to local taxes which are calculated during checkout. Jarno Drost. Study on drug screening multicellular model for colorectal cancer constructed by three-dimensional bioprinting technology. Garman, K. S., Orlando, R. C. & Chen, X. Human organoids can be established from patient- or human-induced pluripotent stem cells that are either cancerous, precancerous, normal, or genome-edited. Get what matters in cancer research, free to your inbox weekly. The success of physiology-related organoid culture has greatly advanced the translational medicine research in the field of cancer . Consequently, the ability to establish 2D monolayers from epithelial-derived organoids allows functional experiments to be carried out, such as wound healing and transepithelial electrical resistance assays to measure functional permeability, while maintaining the unique characteristics of ex vivo organoid cultures, such as molecular identity to the original tissue and presence of a number of different epithelial cell types, such as parietal, chief and mucous neck surface mucosal cells from the stomach (Fig. Nat. Natl Acad. Braverman, J. Careers. Summary. Long-term in vitro expansion of salivary gland stem cells driven by wnt signals. 1 Introduction These adjuvant or neoadjuvant therapies are lifesaving, but increase the risk of life-long complications such as lymphoedema. Organoids can also recapitulate the spatial arrangement of their tissue of origin. Nevertheless, novel and innovative model systems can improve the translational success of preclinical studies, and the methodology for tumour-derived organoid cultures has consequently emerged (Fig. Lugli, N. et al. 2018 Feb 1;414:174-180. doi: 10.1016/j.canlet.2017.11.021. 2022 Mar 19;18:164-177. doi: 10.1016/j.bioactmat.2022.03.020. This study is the first to exploit genome sequencing of clonal organoids as a tool to study mutational processes. 17, 254268 (2017). Our goal is to demonstrate the power and utility of organoid models and provide guidance for investigators who are considering implementation of these models in their own research programs. Tejero, R., Huang, Y., Katsyv, I., Kluge, M., Lin, J. Y., Tome-Garcia, J. et al. Cell 161, 933945 (2015). CAS Ann. USA 116, 1563515644 (2019). Biophys. Defining key concepts of intestinal and epithelial cancer biology through the use of mouse models. and H.C. are named as inventors on several patents related to leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)+ stem cell-based organoid technology. Organoids are a new 3D ex vivo culture system that have been applied in various fields of biomedical research.
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