Emerging organoid models: leaping forward in cancer research

Fan et al. Journal of Hematology & Oncology https://doi.org/10.1186/s13045-019-0832-4 (2019) 12:142 REVIEW Open Access Emerging organoid models: leaping forward in cancer research Han Fan1,2, Utkan Demirci3* and Pu Chen1,2* Abstract Cancer heterogeneity is regarded as the main reason for the failure of conventional cancer therapy. The ability to reconstruct intra- and interpatient heterogeneity in cancer models is crucial for understanding cancer biology as well as for developing personalized anti-cancer therapy. Cancer organoids represent an emerging approach for creating patient-derived in vitro cancer models that closely recapitulate the pathophysiological features of natural tumorigenesis and metastasis. Meanwhile, cancer organoids have recently been utilized in the discovery of personalized anti-cancer therapy and prognostic biomarkers. Further, the synergistic combination of cancer organoids with organ-on-a-chip and 3D bioprinting presents a new avenue in the development of more sophisticated and optimized model systems to recapitulate complex cancer-stroma or multiorgan metastasis. Here, we summarize the recent advances in cancer organoids from a perspective of the in vitro emulation of natural cancer evolution and the applications in personalized cancer theranostics. We also discuss the challenges and trends in reconstructing more comprehensive cancer models for basic and clinical cancer research. Keywords: Cancer organoids, Patient-derived tumor organoids, In vitro model system, Cancer heterogeneity, Personalized anti-cancer therapy, Organ-on-a-chip, 3D Bioprinting Introduction Cancer leads to one in seven deaths worldwide. With the increase in the aging population, the global cancer burden is expected to rise to 21.7 million new cases and 13 million deaths by 2030, according to a recent WHO report [1]. While substantial progress has been made in standard anti-cancer treatment strategies, the effective treatments are still severely lacking primarily due to the tumor heterogeneity between and within individual patients. The tumor heterogeneity results in significant differences in the tumor growth rate, invasion ability, drug sensitivity, and prognosis among individual patients [2]. Therefore, the establishment of a high-fidelity preclinical cancer model is urgently needed to provide precise insights into cancer-related molecular evolution patterns in basic research and to allow personalized anti-cancer therapy in clinical. * Correspondence: ; 3 Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA 94304, USA 1 Department of Biomedical Engineering, Wuhan University School of Basic Medical Sciences, 115 Donghu Road, Wuhan 430071, Hubei, China Full list of author information is available at the end of the article Currently, immortalized cancer cell lines and patientderived tumor xenografts (PDTXs) are commonly used in human cancer research. Cancer cell lines, which are characterized by low cost and ease of use, have been broadly employed in the high-throughput screening of drug candidates and cancer biomarkers. However, cancer cell lines can be only constructed from a limited number of cancer subtypes [3]. Moreover, the tumorspecific heterogeneity of cancer cell lines is gradually lost through epigenetic and genetic drift in the long-term culture [4]. In contrast, PDTXs retain tumor heterogeneity and genomic stability during the passage [5]. Besides, PDTXs can reproduce complex cancer-stroma and cancer-matrix interactions in vivo [6]. Nevertheless, the process of generating PDTX models usually takes more than 4 months, which may not be amenable for aiding terminal cancer patients. Additionally, PDTX models are expensive, labor-intensive, and incompatible with standard procedures in the high-throughput drug screening in the pharmaceutical industry (Table 1) [17–19]. Recently, the emergence of cancer organoid technology with the intrinsic advantage of retaining the heterogeneity of original tumors has provided a unique © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fan et al. Journal of Hematology & Oncology (2019) 12:142 Page 2 of 10 Table 1 Advantages and disadvantages of using PTDX models and cancer organoids for cancer research Feature PDTX models Cancer organoids Generation efficiency 10%–70% [7, 8] 70%–100% Tumor tissue source Surgically resected specimens Surgically resected or biopsy needle specimens Retention of heterogeneity Retention Retention Generation time 4–8 months 4–12 weeks [9–12] Passage efficiency Low High Genetic manipulation Not amenable Amenable High-throughput screening for drug discovery No Yes Immune components Without Retention [13–16] Cost High Low opportunity to improve basic and clinical cancer research [20]. The generation of cancer organoids is low cost, ease of use, and can be accomplished in around 4 weeks [21, 22]. Additionally, tumor organoid culture can be performed in the microplates which are compatible with standard high-throughput assays. Using the geneediting technique, normal organoids can be mutated into tumor organoids, which may emulate genetic alterations during cancer initiation and progression. Currently, various patient-derived tumor organoids (PDTOs) have been generated, including liver, colorectal, pancreatic, and prostate cancer organoids (Table 2) [28, 29, 34, 35]. In this review, we provide an in-depth discussion of cancer organoids for basic cancer research, including carcinogenesis and cancer metastasis. Following this, we describe that the patient-derived cancer organoids offer a revolutionary approach for drug screening, immunotherapy, prognosisrelated hallmark discovery. Finally, we conclude the pros and cons of cancer organoid and propose strategies for enhancing the fidelity of organoid in cancer research (Fig. 1). Organoids for studying carcinogenesis Carcinogenesis occurs through a temporal accumulation of cancer-specific genetic alterations in normal cells [36, 37]. However, the detailed process of genetic mutation in carcinogenesis is elusive. The in-depth investigation Table 2 Cancer organoid models: published reports Tumor organoid model Cell derived Research means Breast cancer organoids Patient Quantitative optical imaging Predict the therapeutic response of anti-tumor drug in individual patients (...truncated)