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      Toward improved in vitro models of human cancer

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          Abstract

          Cancer is a leading cause of death across the world and continues to increase in incidence. Despite years of research, multiple tumors (e.g., glioblastoma, pancreatic cancer) still have limited treatment options in the clinic. Additionally, the attrition rate and cost of drug development have continued to increase. This trend is partly explained by the poor predictive power of traditional in vitro tools and animal models. Moreover, multiple studies have highlighted that cell culture in traditional Petri dishes commonly fail to predict drug sensitivity. Conversely, animal models present differences in tumor biology compared with human pathologies, explaining why promising therapies tested in animal models often fail when tested in humans. The surging complexity of patient management with the advent of cancer vaccines, immunotherapy, and precision medicine demands more robust and patient-specific tools to better inform our understanding and treatment of human cancer. Advances in stem cell biology, microfluidics, and cell culture have led to the development of sophisticated bioengineered microscale organotypic models (BMOMs) that could fill this gap. In this Perspective, we discuss the advantages and limitations of patient-specific BMOMs to improve our understanding of cancer and how these tools can help to confer insight into predicting patient response to therapy.

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          Most cited references102

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          The epithelial-mesenchymal transition generates cells with properties of stem cells.

          The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. We here report that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers. Furthermore, we show that those cells have an increased ability to form mammospheres, a property associated with mammary epithelial stem cells. Independent of this, stem cell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those of HMLEs that have undergone an EMT. Moreover, stem-like cells isolated either from mouse or human mammary glands or mammary carcinomas express EMT markers. Finally, transformed human mammary epithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors more efficiently. These findings illustrate a direct link between the EMT and the gain of epithelial stem cell properties.
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            Fundamentals of cancer metabolism

            Researchers provide a conceptual framework to understand current knowledge of the fundamentals of cancer metabolism.
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              Prospective derivation of a living organoid biobank of colorectal cancer patients.

              In Rspondin-based 3D cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. We report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely recapitulate several properties of the original tumor. The spectrum of genetic changes within the "living biobank" agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell-line- and xenograft-based drug studies, and allow personalized therapy design. PAPERCLIP.
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                Author and article information

                Contributors
                Journal
                APL Bioeng
                APL Bioeng
                ABPID9
                APL Bioengineering
                AIP Publishing LLC
                2473-2877
                March 2021
                21 January 2021
                21 January 2021
                : 5
                : 1
                : 010902
                Affiliations
                [1 ]Department of Biomedical Engineering, University of Wisconsin , Madison, Wisconsin 53705, USA
                [2 ]The University of Wisconsin Carbone Cancer Center, University of Wisconsin , Madison, Wisconsin 53706, USA
                [3 ]Department of Surgery, University of California San Francisco , San Francisco, California 94143, USA
                [4 ]Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705, USA
                Author notes
                [a) ] Author to whom correspondence should be addressed: djbeebe@ 123456wisc.edu . Tel.: (608) 262-2260
                Author information
                https://orcid.org/0000-0002-9414-1845
                https://orcid.org/0000-0003-3660-8651
                https://orcid.org/0000-0002-0415-9006
                Article
                5.0026857 APB20-PS-00116
                10.1063/5.0026857
                7822630
                33532672
                f225f6dd-1d72-4eed-8dea-74b5513b5b65
                © 2021 Author(s).

                2473-2877/2021/5(1)/010902/7

                All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 September 2020
                : 30 November 2020
                Page count
                Pages: 7
                Funding
                Funded by: Wisconsin Head and Neck Cancer SPORE
                Award ID: P50DE026787
                Funded by: Morgridge Institute for Research
                Award ID: -
                Funded by: National Cancer Institute https://doi.org/10.13039/100000054
                Award ID: R01EB010039
                Funded by: National Cancer Institute https://doi.org/10.13039/100000054
                Award ID: 5T32HL110853-07
                Funded by: University of Wisconsin Carbone Cancer Center https://doi.org/10.13039/100007923
                Award ID: P30CA014520
                Categories
                Perspectives
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