RT Journal Article
SR Electronic
T1 A multidimensional atlas of human glioblastoma organoids reveals highly coordinated molecular networks and effective drugs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.24.525374
DO 10.1101/2023.01.24.525374
A1 Changwen Wang
A1 Meng Sun
A1 Chunxuan Shao
A1 Lisa Schlicker
A1 Yue Zhuo
A1 Yassin Harim
A1 Tianping Peng
A1 Weili Tian
A1 Nadja Stöffler
A1 Martin Schneider
A1 Dominic Helm
A1 Jan-Philipp Mallm
A1 Yonghe Wu
A1 Almut Schulze
A1 Hai-Kun Liu
YR 2023
UL http://biorxiv.org/content/early/2023/01/24/2023.01.24.525374.abstract
AB 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 organoid (LEGO: Laboratory Engineered Glioblastoma Organoid) 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 novel human GBM models and a research path toward effective GBM therapy.Competing Interest StatementThe authors have declared no competing interest.