Home > Unraveling Intratumoral Heterogeneity and Treatment Resistance in Malignant Glioma through Multi-omics Analysis
Unraveling Intratumoral Heterogeneity and Treatment Resistance in Malignant Glioma through Multi-omics Analysis
Despite advances in cancer medicine, brain tumors remain among the most challenging diseases to treat. In recent years, the development of sequencing technologies has significantly improved our understanding of how brain tumors evolve and progress.
It is now known that tumors typically originate from specific genetic alterations. Following tumor initiation, different tumor cell populations independently acquire additional mutations and adapt to their surrounding microenvironment, including therapeutic intervention. This phenomenon, known as intratumoral heterogeneity, has been increasingly recognized as a key contributor to tumor progression and treatment resistance.
To investigate this, we conducted multi-regional sampling of lower-grade gliomas (LGGs, WHO Grade II and III), collecting tissue samples from multiple sites within the same tumor. Using high-depth, comprehensive genomic analyses, we successfully reconstructed the clonal architecture of LGGs (Suzuki H et al., Nature Genetics 47(5):458-468, 2015). Our study revealed that LGGs harbor substantial intratumoral heterogeneity, where distinct clones evolve independently with unique genetic changes across both space and time.
We also found that mutations in IDH1/2 and 1p/19q codeletion occur at the earliest stage of tumor development and remain consistent across the tumor mass. These stable early events highlight their utility as reliable diagnostic markers.
This was the first study in the world to comprehensively analyze the genomic landscape and clonal diversity of LGGs, and its findings have been incorporated into the 2016 and 2021 editions of the WHO Classification of Central Nervous System Tumors.
Thanks to recent technological advancements, we can now investigate these beyond-genetic layers of regulation more comprehensively. In our research, we apply a multi-omics approach to dissect the complexity of brain tumors.
By integrating multi-layer datasets, we aim to uncover the molecular drivers that lead to malignant transformation and treatment resistance in gliomas.
In addition, we are utilizing cutting-edge single-cell analysis technologies to investigate gene expression and epigenetic regulation at the resolution of individual cells. This enables us to capture the full extent of cellular diversity within gliomas and identify subpopulations of tumor cells with aggressive features, such as high invasiveness and resistance to therapy.
Through this comprehensive, high-resolution analysis, we strive to elucidate the mechanisms that fuel tumor progression and to discover novel therapeutic targets for treating malignant gliomas.
It is now known that tumors typically originate from specific genetic alterations. Following tumor initiation, different tumor cell populations independently acquire additional mutations and adapt to their surrounding microenvironment, including therapeutic intervention. This phenomenon, known as intratumoral heterogeneity, has been increasingly recognized as a key contributor to tumor progression and treatment resistance.
To investigate this, we conducted multi-regional sampling of lower-grade gliomas (LGGs, WHO Grade II and III), collecting tissue samples from multiple sites within the same tumor. Using high-depth, comprehensive genomic analyses, we successfully reconstructed the clonal architecture of LGGs (Suzuki H et al., Nature Genetics 47(5):458-468, 2015). Our study revealed that LGGs harbor substantial intratumoral heterogeneity, where distinct clones evolve independently with unique genetic changes across both space and time.
We also found that mutations in IDH1/2 and 1p/19q codeletion occur at the earliest stage of tumor development and remain consistent across the tumor mass. These stable early events highlight their utility as reliable diagnostic markers.
This was the first study in the world to comprehensively analyze the genomic landscape and clonal diversity of LGGs, and its findings have been incorporated into the 2016 and 2021 editions of the WHO Classification of Central Nervous System Tumors.
Beyond Genetic Mutations: Decoding the Epigenetic and Transcriptomic Drivers of Tumor Progression
While intratumoral heterogeneity has been increasingly recognized as a key factor in tumor progression and treatment resistance, the precise mechanisms by which this diversity leads to malignancy remain poorly understood. One primary reason is that most previous studies have focused primarily on genetic alterations. However, recent findings suggest that tumor heterogeneity also arises from abnormalities in transcriptomic/epigenetic modifications, such as DNA methylation and chromatin structure and alterations in RNA processing and protein regulation.Thanks to recent technological advancements, we can now investigate these beyond-genetic layers of regulation more comprehensively. In our research, we apply a multi-omics approach to dissect the complexity of brain tumors.
By integrating multi-layer datasets, we aim to uncover the molecular drivers that lead to malignant transformation and treatment resistance in gliomas.
In addition, we are utilizing cutting-edge single-cell analysis technologies to investigate gene expression and epigenetic regulation at the resolution of individual cells. This enables us to capture the full extent of cellular diversity within gliomas and identify subpopulations of tumor cells with aggressive features, such as high invasiveness and resistance to therapy.
Through this comprehensive, high-resolution analysis, we strive to elucidate the mechanisms that fuel tumor progression and to discover novel therapeutic targets for treating malignant gliomas.
