A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs

NPJ Precis Oncol. 2024 Jan 26;8(1):19. doi: 10.1038/s41698-024-00500-5.

Changwen Wang ^# ¹ ² ³, Meng Sun ^# ⁴ ⁵, Chunxuan Shao ⁶, Lisa Schlicker ⁷ ⁸, Yue Zhuo ⁶ ⁹, Yassin Harim ⁶ ⁹, Tianping Peng ⁴ ⁵, Weili Tian ⁶, Nadja Stöffler ⁶, Martin Schneider ⁸, Dominic Helm ⁸, Youjun Chu ⁴, Beibei Fu ⁴ ⁵, Xiaoliang Jin ¹⁰ ¹¹, Jan-Philipp Mallm ¹², Moritz Mall ¹³ ¹⁴ ¹⁵, Yonghe Wu ⁴, Almut Schulze ⁷, Hai-Kun Liu ¹⁶ ¹⁷

Affiliations

1 Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ); The DKFZ-ZMBH alliance, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. [email protected].
2 Faculty of Medicine, Heidelberg University, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany. [email protected].
3 Department of Thyroid Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China. [email protected].
4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210, Shanghai, China.
5 School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China.
6 Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ); The DKFZ-ZMBH alliance, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
7 Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
8 Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
9 Faculty of Biosciences, Heidelberg University, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany.
10 Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
11 Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, 200025, Shanghai, China.
12 Single-cell Open Lab, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
13 Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120, Heidelberg, Germany.
14 HITBR Hector Institute for Translational Brain Research gGmbH, 69120, Heidelberg, Germany.
15 Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159, Mannheim, Germany.
16 Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ); The DKFZ-ZMBH alliance, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. [email protected].
17 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210, Shanghai, China. [email protected].
# Contributed equally.

PMID: 38273014 DOI: 10.1038/s41698-024-00500-5

Abstract

Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM-like organoid (LEGO: Laboratory Engineered Glioblastoma-like Organoid) models and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides new human GBM models and a research path toward effective GBM therapy.

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