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      Organ-on-a-Chip for Cancer and Immune Organs Modeling

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          Abstract

          Bridging the gap between findings in preclinical 2D cell culture models and in vivo tissue cultures has been challenging; the simple microenvironment of 2D monolayer culture systems may not capture the cellular response to drugs accurately. Three-dimensional organotypic models have gained increasing interest due to their ability to recreate precise cellular organizations. These models facilitate investigation of the interactions between different sub-tissue level components through providing physiologically relevant microenvironments for cells in vitro. The incorporation of human-sourced tissues into these models further enables personalized prediction of drug responses. Integration of microfluidic units into the 3D models can be used to control their local environment, dynamic simulation of cell behaviors, and real-time readout of drug testing data. Cancer and immune system related diseases are severe burdens to our health care system and have created an urgent need for high-throughput, and effective drug development plans. This review focuses on recent progress in the development of "cancer-on-a-chip" and "immune organs-on-a-chip" systems designed to study disease progression and predict drug-induced responses. Future challenges and opportunities are also discussed.

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          Most cited references79

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          Human Primary Liver Cancer -derived Organoid Cultures for disease modelling and drug screening

          Human liver cancer research currently lacks in vitro models that faithfully recapitulate the pathophysiology of the original tumour. We recently described a novel, near-physiological organoid culture system, where primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here, we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumours. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumour, allowing discrimination between different tumour tissues and subtypes, even after long term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumourogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug screening testing and lead to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized medicine approaches for the disease.
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            Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids.

            Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT, MAPK, TGF-β, TP53 and PI3K pathways. Although these pathways influence intestinal stem cell niche signaling, the extent to which mutations in these pathways contribute to human colorectal carcinogenesis remains unclear. Here we use the CRISPR-Cas9 genome-editing system to introduce multiple such mutations into organoids derived from normal human intestinal epithelium. By modulating the culture conditions to mimic that of the intestinal niche, we selected isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, and in the oncogenes KRAS and/or PIK3CA. Organoids engineered to express all five mutations grew independently of niche factors in vitro, and they formed tumors after implantation under the kidney subcapsule in mice. Although they formed micrometastases containing dormant tumor-initiating cells after injection into the spleen of mice, they failed to colonize in the liver. In contrast, engineered organoids derived from chromosome-instable human adenomas formed macrometastatic colonies. These results suggest that 'driver' pathway mutations enable stem cell maintenance in the hostile tumor microenvironment, but that additional molecular lesions are required for invasive behavior.
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              Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5⁺ stem cell.

              Adult stem-cell therapy holds promise for the treatment of gastrointestinal diseases. Here we describe methods for long-term expansion of colonic stem cells positive for leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5(+) cells) in culture. To test the transplantability of these cells, we reintroduced cultured GFP(+) colon organoids into superficially damaged mouse colon. The transplanted donor cells readily integrated into the mouse colon, covering the area that lacked epithelium as a result of the introduced damage in recipient mice. At 4 weeks after transplantation, the donor-derived cells constituted a single-layered epithelium, which formed self-renewing crypts that were functionally and histologically normal. Moreover, we observed long-term (>6 months) engraftment with transplantation of organoids derived from a single Lgr5(+) colon stem cell after extensive in vitro expansion. These data show the feasibility of colon stem-cell therapy based on the in vitro expansion of a single adult colonic stem cell.
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                Author and article information

                Journal
                Advanced Healthcare Materials
                Adv. Healthcare Mater.
                Wiley
                21922640
                January 03 2019
                : 1801363
                Affiliations
                [1 ]Department of Bioengineering; University of California-Los Angeles; Los Angeles CA 90095 USA
                [2 ]Center for Minimally Invasive Therapeutics (C-MIT); California NanoSystems Institute; University of California-Los Angleles; Los Angeles CA 90095 USA
                [3 ]School of Pharmacy; Xi'an Jiaotong University; Xi'an 710061 China
                [4 ]College of Chemistry; Nankai University; Tianjin 300071 China
                [5 ]Department of Chemical and Biomolecular Engineering; University of California-Los Angeles; Los Angeles CA 90095 USA
                [6 ]Brigham and Women's Hospital; Harvard Medical School; Boston MA 02115 USA
                [7 ]Harvard-MIT Division of Health Sciences and Technology; Cambridge MA 02139 USA
                [8 ]Jonsson Comprehensive Cancer Center; University of California-Los Angeles; 10833 Le Conte Ave Los Angeles CA 90024 USA
                [9 ]Department of Radiology; University of California-Los Angeles; Los Angeles CA 90095 USA. Department of Bioindustrial Technologies; College of Animal Bioscience and Technology; Konkuk University; Seoul 143701 Republic of Korea
                Article
                10.1002/adhm.201801363
                6424124
                30605261
                29f860ee-cce8-4c0b-a9d0-2bafcc1c9ec8
                © 2019

                http://doi.wiley.com/10.1002/tdm_license_1.1

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