A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity

Fadi Jacob; Ryan D Salinas; Daniel Y Zhang; Phuong T T Nguyen; Jordan G Schnoll; Samuel Zheng Hao Wong; Radhika Thokala; Saad Sheikh; Deeksha Saxena; Stefan Prokop; Di-Ao Liu; Xuyu Qian; Dmitriy Petrov; Timothy Lucas; H Isaac Chen; Jay F Dorsey; Kimberly M Christian; Zev A Binder; MacLean Nasrallah; Steven Brem; Donald M O'Rourke; Guo-Li Ming; Hongjun Song

doi:10.1016/j.cell.2019.11.036

A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity

Cell. 2020 Jan 9;180(1):188-204.e22. doi: 10.1016/j.cell.2019.11.036. Epub 2019 Dec 26.

Authors

Fadi Jacob¹, Ryan D Salinas², Daniel Y Zhang³, Phuong T T Nguyen⁴, Jordan G Schnoll⁵, Samuel Zheng Hao Wong⁶, Radhika Thokala², Saad Sheikh⁷, Deeksha Saxena⁷, Stefan Prokop⁸, Di-Ao Liu⁹, Xuyu Qian¹⁰, Dmitriy Petrov², Timothy Lucas², H Isaac Chen¹¹, Jay F Dorsey¹², Kimberly M Christian⁵, Zev A Binder¹³, MacLean Nasrallah¹², Steven Brem¹³, Donald M O'Rourke¹⁴, Guo-Li Ming¹⁵, Hongjun Song¹⁶

Affiliations

¹ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Bioengineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹¹ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA.
¹² Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Glioblastoma Translational Center of Excellence, The Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹³ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA; Glioblastoma Translational Center of Excellence, The Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA; Glioblastoma Translational Center of Excellence, The Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: donald.orourke@pennmedicine.upenn.edu.
¹⁵ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: ming@pennmedicine.upenn.edu.
¹⁶ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Glioblastoma Translational Center of Excellence, The Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.

Abstract

Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.

Keywords: CAR-T cells; Organoid; biobank; cancer modeling; drug testing; glioblastoma; personalized therapies; translational; tumor heterogeneity; xenograft.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Biological Specimen Banks
Cell Culture Techniques / methods*
Female
Glioblastoma / genetics
Glioblastoma / metabolism*
Glioblastoma / pathology
Humans
Male
Mice
Mice, Nude
Middle Aged
Models, Biological
Organoids / growth & development*
Organoids / metabolism
Reproducibility of Results
Xenograft Model Antitumor Assays / methods

Abstract

Publication types

MeSH terms

Grants and funding