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Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2024) 17, dmm050533 . doi:10 . 1242/dmm.050533  \nSPECIAL ARTICLE  \nStem cell modeling of nervous system tumors  \nFrank B. Furnari1,*, Corina Anastasaki2, Shan Bian3, Howard A. Fine4, Tomoyuki Koga5, Lu Q. Le6, Fausto J. Rodriguez7 and David H. Gutmann2,*  \nABSTRACT  \nNervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumorsin adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations associated with nervous system cancers can be introduced. These stem cells can be used to create self-assembling three-dimensional cerebral organoids that preserve key features of the developing human brain. Moreover, stem cell-engineered lines are amenable toxenotransplantation into mice as a platform to investigate the tumor cell of origin, discover cancer evolutionary trajectories and identify therapeutic vulnerabilities. In this article, we review the current state of human stem cell models of nervous system tumors, discuss their advantages and disadvantages, and provide consensus recommendations for future research.  \nKEY WORDS: CRISPR engineering, Brain tumor, human embryonic stem cells (hESCs), human induced pluripotent stem cells (hiPSCs), Nerve sheath tumors  \nIntroduction  \nCancer is one of the leading causes of death in children and adults, prompting the National Cancer Institute to launch the Cancer Moonshot initiative in 2016, with the goal of reducing cancer death, and improving the lives of people with cancer and cancer survivors. With the reinvigoration of this initiative in 2022 (Bertagnolli et al., 2023; Shiels et al., 2023), the development of therapeutic approaches to benefit those living with cancer has accelerated.  \n1Department of Medicine, University of California, San Diego, San Diego,  \nCA 92037, USA. 2Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. 3Institute for Regenerative Medicine, School of Life Sciences and Technology, Tongji University, 200070 Shanghai, China. 4Department of Neurology, Weill Cornell Medicine, New York, NY 10065, USA. 5Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA. 6Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 7Division of Neuropathology, University of California, Los Angeles, Los Angeles, CA 90095, USA.  \n*Authors for correspondence ([gutmannd@wustl.edu](gutmannd@wustl.edu); [ffurnari@ucsd.edu](ffurnari@ucsd.edu))  \n F. B. F. , 0000-0003-1909-4361; C.A. , 0000-0002-9928-6488; H.A. F. , 0000-0002- 6169-5702; T. K. , 0000-0002-8330-117X; L. Q. L. , 0000-0003-2817-5382; D. H. G. , 0000-0002-3127-5045  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0](https://creativecommons.org/licenses/by/4.0)), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.  \nReceived 1 October 2023; Accepted 18 December 2023  \nOne of the major areas of focus is increasing the pipeline of new cancer drugs and accelerating their translation to the clinical workplace. To address this challenge, there is a pressing need to develop platforms amenable to rapid drug screening and therapeutic validation. In the past, lead compounds were identified using immortalized cancer c","cbCaisY5xBlJaZQ6","https://ap.wps.com/l/cbCaisY5xBlJaZQ6","pdf",1056178,13,"English","# Abstract\n# Introduction\n# Cancer drug development and the need for rapid screening platforms\n# Limitations of traditional cell line and patient-derived models\n# Advantages and limitations of genetically engineered mouse models\n# Challenges replicating specific human genetic alterations","[{\"question\":\"Why are stem cell models increasingly important for nervous system tumors?\",\"answer\":\"Traditional platforms such as human tumor cells and genetically engineered mouse models are limited in reproducing important features of spontaneously arising human tumors. Human stem cell engineering provides engineered, human-relevant systems for studying tumor biology and therapies.\"},{\"question\":\"How can engineered stem cells be used to study tumor development?\",\"answer\":\"Engineered human stem cells can be used to generate self-assembling three-dimensional cerebral organoids and to perform xenotransplantation into mice, enabling investigation of tumor origins, evolutionary trajectories, and therapeutic vulnerabilities.\"},{\"question\":\"What limitations do immortalized cancer cell lines have for therapy discovery?\",\"answer\":\"Immortalized lines do not resemble their native parental tumors, lack dependence on stroma, and can accumulate additional genetic or molecular changes during extensive in vitro passaging.\"}]","Stem cell modeling of nervous system tumors | PDF",1789995551,33]