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      Sarcoma Spheroids and Organoids—Promising Tools in the Era of Personalized Medicine

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          Abstract

          Cancer treatment is rapidly evolving toward personalized medicine, which takes into account the individual molecular and genetic variability of tumors. Sophisticated new in vitro disease models, such as three-dimensional cell cultures, may provide a tool for genetic, epigenetic, biomedical, and pharmacological research, and help determine the most promising individual treatment. Sarcomas, malignant neoplasms originating from mesenchymal cells, may have a multitude of genomic aberrations that give rise to more than 70 different histopathological subtypes. Their low incidence and high level of histopathological heterogeneity have greatly limited progress in their treatment, and trials of clinical sarcoma are less frequent than trials of other carcinomas. The main advantage of 3D cultures from tumor cells or biopsy is that they provide patient-specific models of solid tumors, and they overcome some limitations of traditional 2D monolayer cultures by reflecting cell heterogeneity, native histologic architectures, and cell–extracellular matrix interactions. Recent advances promise that these models can help bridge the gap between preclinical and clinical research by providing a relevant in vitro model of human cancer useful for drug testing and studying metastatic and dormancy mechanisms. However, additional improvements of 3D models are expected in the future, specifically the inclusion of tumor vasculature and the immune system, to enhance their full ability to capture the biological features of native tumors in high-throughput screening. Here, we summarize recent advances and future perspectives of spheroid and organoid in vitro models of rare sarcomas that can be used to investigate individual molecular biology and predict clinical responses. We also highlight how spheroid and organoid culture models could facilitate the personalization of sarcoma treatment, provide specific clinical scenarios, and discuss the relative strengths and limitations of these models.

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          Organoids as an in vitro model of human development and disease.

          The in vitro organoid model is a major technological breakthrough that has already been established as an essential tool in many basic biology and clinical applications. This near-physiological 3D model facilitates an accurate study of a range of in vivo biological processes including tissue renewal, stem cell/niche functions and tissue responses to drugs, mutation or damage. In this Review, we discuss the current achievements, challenges and potential applications of this technique.
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            Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine.

            Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board-approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted.Significance: Integration of genomic data with drug screening from personalized in vitro and in vivo cancer models guides precision cancer care and fuels next-generation research. Cancer Discov; 7(5); 462-77. ©2017 AACR.See related commentary by Picco and Garnett, p. 456This article is highlighted in the In This Issue feature, p. 443.
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              3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained

              The potential of a spheroid tumor model composed of cells in different proliferative and metabolic states for the development of new anticancer strategies has been amply demonstrated. However, there is little or no information in the literature on the problems of reproducibility of data originating from experiments using 3D models. Our analyses, carried out using a novel open source software capable of performing an automatic image analysis of 3D tumor colonies, showed that a number of morphology parameters affect the response of large spheroids to treatment. In particular, we found that both spheroid volume and shape may be a source of variability. We also compared some commercially available viability assays specifically designed for 3D models. In conclusion, our data indicate the need for a pre-selection of tumor spheroids of homogeneous volume and shape to reduce data variability to a minimum before use in a cytotoxicity test. In addition, we identified and validated a cytotoxicity test capable of providing meaningful data on the damage induced in large tumor spheroids of up to diameter in 650 μm by different kinds of treatments.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                21 February 2018
                February 2018
                : 19
                : 2
                : 615
                Affiliations
                [1 ]Division of Orthopedic Surgery, Department of Human Health, Federico II University of Naples, 80133 Naples, Italy; glc.colella@ 123456gmail.com (G.C.); Carlo.ruosi@ 123456gmail.com (C.R.)
                [2 ]Division of Musculoskeletal Oncology Surgery, National Cancer Institute, Pascale Foundation, 80131 Naples, Italy; F.fazioli@ 123456istitutotumori.na.it (F.F.); miga76@ 123456alice.it (M.G.)
                [3 ]Division of Pathology, National Cancer Institute, Pascale Foundation, 80131 Naples, Italy; anna.dechiara@ 123456istitutotumori.na.it
                [4 ]Division of Medical Oncology, National Cancer Institute, Pascale Foundation, 80131 Naples, Italy; g.apice@ 123456istitutotumori.na.it
                [5 ]Institute of Genetics and Biophysics “A. Buzzati Traverso”, National Research Council (CNR), 80131 Naples, Italy; amelia.cimmino@ 123456gmail.it
                [6 ]Department of Biochemistry Biophysics and General Pathology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-2322-1557
                Article
                ijms-19-00615
                10.3390/ijms19020615
                5855837
                29466296
                91bf5b7d-4dde-472c-9496-adb9afe00153
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 December 2017
                : 16 February 2018
                Categories
                Review

                Molecular biology
                spheroids,tumor microenvironment,sarcomas,precision medicine,personalized medicine

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