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      Biofabrication of advanced in vitro and ex vivo cancer models for disease modeling and drug screening

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          Abstract

          Bioengineered in vitro models have advanced from 2D cultures and simple 3D cell aggregates to more complex organoids and organ-on-a-chip platforms. This shift has been substantial in cancer research; while simple systems remain in use, multi-tissue type tumor and tissue chips and patient-derived tumor organoids have grown rapidly. These more advanced models offer new tools to cancer researchers based on human tumor physiology and the potential for interactions with nontumor tissue physiology while avoiding critical differences between human and animal biology. In this focused review, the authors discuss the importance of organoid and organ-on-a-chip platforms, with a particular focus on modeling cancer, to highlight oncology-focused in vitro model platform technologies that improve upon the simple 2D cultures and 3D spheroid models of the past.

          Lay Abstract

          Cancer research has recently benefited from advancements in bioengineered 3D models, such as tumor organoids and tumor-on-a-chip systems. These kinds of models can be human-based, thus allowing for human physiology-based cancer studies to be performed, as opposed to relying on animal models. In this focused review, the authors discuss the importance of organoid and organ-on-a-chip platforms, with a particular focus on modeling cancer.

          Most cited references76

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          Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

          The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
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            Tensional homeostasis and the malignant phenotype.

            Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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              Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.

              Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.
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                Author and article information

                Journal
                FDD
                Future Drug Discovery
                Future Drug. Discov.
                Future Drug Discovery
                Newlands Press Ltd (London, UK )
                2631-3316
                03 September 2021
                September 2021
                : 3
                : 3
                : FDD62
                Affiliations
                1Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA
                2Arthur G. James Comprehensive Cancer Center & The Ohio State University & Columbus, OH 43210, USA
                Author notes
                [* ]Author for correspondence: Tel.: 01614 504 3226; skardal.1@ 123456osu.edu
                Author information
                https://orcid.org/0000-0002-2138-2453
                Article
                10.4155/fdd-2020-0034
                d8a0aaf8-0cad-4bb6-b519-8a37edaa26d8
                © Aleksander Skardal

                This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License

                History
                : 16 December 2020
                : 29 July 2021
                : 03 September 2021
                Page count
                Pages: 12
                Funding
                Funded by: National Center for Advancing Translational Sciences http://dx.doi.org/10.13039/100006108
                Award ID: Clinical and Translational Science Institute at Wa
                Funded by: National Cancer Institute http://dx.doi.org/10.13039/100000054
                Award ID: 1R21CA229027
                Categories
                Review

                Biochemistry,Molecular medicine,Pharmaceutical chemistry,Bioinformatics & Computational biology,Biotechnology,Pharmacology & Pharmaceutical medicine
                biofabrication,tumor-on-a-chip,precision medicine,premetastatic niche,organoids,cancer models

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