Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

in Cell by Radhika Mathur, Qixuan Wang, Patrick G Schupp, Ana Nikolic, Stephanie Hilz, Chibo Hong, Nadia R Grishanina, Darwin Kwok, Nicholas O Stevers, Qiushi Jin, Mark W Youngblood, Lena Ann Stasiak, Ye Hou, Juan Wang, Takafumi N Yamaguchi, Marisa Lafontaine, Anny Shai, Ivan V Smirnov, David A Solomon, Susan M Chang, Shawn L Hervey-Jumper, Mitchel S Berger, Janine M Lupo, Hideho Okada, Joanna J Phillips, Paul C Boutros, Marco Gallo, Michael C Oldham, Feng Yue, Joseph F Costello

TLDR

  • The study investigates the complexity of a type of brain tumor called glioblastoma (GBM) using advanced technology to map the tumor in 3D. The study found that the tumor is made up of different parts that are not the same and that these parts change over time. The study also found that these changes are related to the way the tumor started and how it grew. The study suggests that these changes could be used as targets for treatment to help stop the tumor from growing.

Abstract

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Overview

  • The study aims to investigate the intratumoral heterogeneity and evolution of glioblastoma (GBM) using 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. The study tests the hypothesis that GBM evolutionary trajectories can be inferred from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The results show that GBM evolutionary trajectories can be inferred from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. The study identifies sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning, which could potentially be used as therapeutic targets to circumvent heterogeneity-related failures.

Implications and Future Directions

  • The study's findings highlight the significance of GBM evolution and heterogeneity from a 3D whole-tumor perspective, which could potentially impact the field of research or clinical practice. The study identifies potential therapeutic targets that might circumvent heterogeneity-related failures. However, the study also identifies limitations that need to be addressed in future research, such as the need for larger sample sizes and the need to validate the findings in independent datasets. Future research directions could build on the results of the study, explore unresolved questions, or utilize novel approaches to further understand GBM evolution and heterogeneity.
Read Full Article