Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy PMID: 39938519

ADC Targets in Oncology

2026-04-10

Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy

Cell Stem Cell. 2025 Apr 3;32(4):652-669.e11. doi: 10.1016/j.stem.2025.01.002.

Tianping Peng ¹ , Xiujian Ma ² , Wei Hua ³ , Changwen Wang ² , Youjun Chu ⁴ , Meng Sun ¹ , Valentina Fermi ⁵ , Stefan Hamelmann ⁶ , Katharina Lindner ⁷ , Chunxuan Shao ² , Julia Zaman ⁶ , Weili Tian ² , Yue Zhuo ² , Yassin Harim ² , Nadja Stöffler ² , Linda Hammann ² , Qungen Xiao ² , Xiaoliang Jin ² , Rolf Warta ⁵ , Catharina Lotsch ⁵ , Xuran Zhuang ⁸ , Yuan Feng ³ , Minjie Fu ³ , Xin Zhang ³ , Jinsen Zhang ³ , Hao Xu ³ , Fufang Qiu ³ , Liqian Xie ³ , Yi Zhang ³ , Wei Zhu ³ , Zunguo Du ⁹ , Lorena Salgueiro ¹⁰ , Mark Schneider ¹¹ , Florian Eichhorn ¹² , Arthur Lefevre ¹³ , Stefan Pusch ⁶ , Valery Grinevich ¹³ , Miriam Ratliff ¹⁴ , Sonja Loges ¹⁵ , Lukas Bunse ⁷ , Felix Sahm ⁶ , Yangfei Xiang ¹⁶ , Andreas Unterberg ⁵ , Andreas von Deimling ⁶ , Michael Platten ¹⁷ , Christel Herold-Mende ⁵ , Yonghe Wu ¹⁸ , Hai-Kun Liu ¹⁹ , Ying Mao ²⁰

Affiliations

1. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
2. Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 581, Heidelberg 69120, Germany.
3. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University; National Center for Neurological Disorders, Shanghai 200040, China.
4. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
5. Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, Heidelberg 69120, Germany.
6. Deptment of Neuropathology, University Hospital Heidelberg, CCU Neuropathology, German Cancer Research Center (DKFZ), University Heidelberg, Heidelberg 69120, Germany.
7. DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Tanslational Neuroscience (MCTN), Heidelberg University, Heidelberg 69120, Germany; Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany.
8. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
9. Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China.
10. DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim 68167, Germany; Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany.
11. Translational Research Unit, Thoraxklinik at Heidelberg University, Heidelberg 69120, Germany; Translational Lung Research Center Heidelberg (TRLC), German Center for Lung Research (DZL), Heidelberg 69120, Germany.
12. Department of Thoracic Surgery, Thoraxklinik, University Hospital Heidelberg, Roentgenstrasse 1, Heidelberg 69126, Germany; Translational Lung Research Center Heidelberg (TRLC), German Center for Lung Research (DZL), Heidelberg 69120, Germany.
13. Department of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany.
14. DKTK Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Research Center (DKFZ), Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim 68167, Germany.
15. DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim 68167, Germany; Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany; Translational Lung Research Center Heidelberg (TRLC), German Center for Lung Research (DZL), Heidelberg 69120, Germany.
16. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
17. DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Helmholtz Institute of Translational Oncology Mainz (HI-TRON Mainz) - a Helmholtz Institute of the DKFZ, Mainz 55131, Germany; Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Tanslational Neuroscience (MCTN), Heidelberg University, Heidelberg 69120, Germany; Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany; German Cancer Consortium (DKTK), DKFZ, Core Center, Heidelberg 69120, Germany.
18. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University; Shanghai Clinical Research and Trial Center, Shanghai 201210, China. Electronic address: [email protected].
19. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 581, Heidelberg 69120, Germany. Electronic address: [email protected].
20. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University; National Center for Neurological Disorders, Shanghai 200040, China. Electronic address: [email protected].

Abstract

Tumor organoids are important tools for Cancer research, but current models have drawbacks that limit their applications for predicting response to therapy. Here, we developed a fast, efficient, and complex culture system (IPTO, individualized patient tumor Organoid) that accurately recapitulates the cellular and molecular pathology of human brain tumors. Patient-derived tumor explants were cultured in induced pluripotent stem cell (iPSC)-derived cerebral organoids, thus enabling culture of a wide range of human tumors in the central nervous system (CNS), including adult, pediatric, and metastatic brain cancers. Histopathological, genomic, epigenomic, and single-cell RNA Sequencing (scRNA-seq) analyses demonstrated that the IPTO model recapitulates cellular heterogeneity and molecular features of original tumors. Crucially, we showed that the IPTO model predicts patient-specific drug responses, including resistance mechanisms, in a prospective patient cohort. Collectively, the IPTO model represents a major breakthrough in preclinical modeling of human cancers, which provides a path toward personalized Cancer therapy.

Keywords

brain metastasis; glioblastoma; patient tumor organoid; predictive patient model; temozolomide; tumor heterogeneity.