Annual Report 2021
Division of Brain Tumor Translational Research
Hiromichi Suzuki, Atsuhito Uneda, Takuma Nakashima, Shohei Nambu, Yusuke Funakoshi, Mai Kitahara, Yuki Yomoda
Introduction
Malignant brain tumors are highly lethal and aggressive. Despite recent advances in the current therapies including the combination of surgical resection, chemotherapy, and radiotherapy, the prognosis remains poor. Therefore, novel molecular therapies with reduced side effects are highly needed. The recent development of sequencing technology enables us to reveal how malignant tumors form and why some of the tumors are refractory to current therapies. We use genetic tools to reveal brain tumor pathogenesis to lead to the development of novel therapies.
The Team and What We Do
Our team’s expertise is in bioinformatics analysis. We are working on sequencing analysis to reveal the detailed mechanisms of brain tumor pathogenesis and discover novel therapeutic targets. Using human tissues resected in surgical resection, cell lines, and mouse models, we are performing multi-omics analyses including genomic, epigenomic, transcriptomic, and post-transcriptomic data. In addition to that basic research, we are working on clinical applications that are able to diagnose brain tumors with high accuracy and low cost based on molecular classification.
We provide bioinformatics analyses for other cancer genome projects, especially for urological cancers.
Research activities
1. Multi-omics analyses of brain tumors
Recent advances in sequencing technology enable us to classify brain tumors based on their molecular features leading to precision medicine. Thus far, we have revealed the mutational landscape of glioma and medulloblastoma. Those findings are now used in the WHO classification (Suzuki, H. Nat Genet, 2015). We have joined the national sequencing project as a team for the rare cancers for which our lab is conducting multi-omics analysis of brain tumors. In this project, our lab performed whole-genome sequencing and RNA-seq for more than 470 cases with brain tumors and is analyzing the sequencing data to discover novel targets using the world’s largest sequencing data from brain tumors.
2. Genetic analysis of medulloblastoma
Medulloblastoma is the most common pediatric malignant brain tumor. We developed a bioinformatics workflow that can detect mutations with high accuracy from RNA-seq data and discovered a novel recurrent mutation in Group 4 medulloblastoma using RNA-seq data. Multi-omics analyses including single-cell RNA-seq and proteomics revealed that the novel mutation inhibits cell differentiation and causes cell rest in early unipolar cells in the subventricular zone in the upper rhombic lip.
We discovered a recurrent mutation in U1 small nuclear RNA (U1 snRNA) in SHH medulloblastoma. U1 snRNA works on RNA processing and has a variety of functions. Its primary function is the recognition of 5′ splice sites. Recently, it has been reported that U1 snRNA has several functions other than splice site recognition. We are developing and analyzing several types of RNA-seq to reveal the mechanism of U1 small nuclear mutation.
3. Analysis of intratumoral heterogeneity in gliomas
Intratumoral heterogeneity contributes to therapy resistance and tumor progression. We are developing single-cell multi-omics methods and analyses for gliomas to reveal intratumoral heterogeneity in gliomas. We are generating high-quality multi-omics single-cell data in collaboration with the Department of Neurosurgery and Neuro-Oncology. Combining publicly available datasets of single-cell sequencing, we are describing evolutional trajectories associated with brain development and seeking transcriptional vulnerability under the tumor progression.
Education
We have trained a post-doctoral researcher and three Ph.D. students.
Future Prospects
The development of sequencing technology enables us to analyze what happens in the cancer cell from the perspective of multi-omics. We are using state-of-art technology to uncover how cancer arises and evolves. As we are generating and collecting the world’s largest sequencing data for brain tumors, we are working on bioinformatic analyses which will discover novel genetic events and findings underlying brain tumor pathogenesis. We are also developing rapid clinical applications to diagnose brain tumors and other cancers which will contribute to the precise diagnosis and the better stratification of patients based on molecular features.
List of papers published in 2021
Journal
1. Aoki K, Suzuki H, Yamamoto T, Yamamoto KN, Maeda S, Okuno Y, Ranjit M, Motomura K, Ohka F, Tanahashi K, Hirano M, Nishikawa T, Shimizu H, Kitano Y, Yamaguchi J, Yamazaki S, Nakamura H, Takahashi M, Narita Y, Nakada M, Deguchi S, Mizoguchi M, Momii Y, Muragaki Y, Abe T, Akimoto J, Wakabayashi T, Saito R, Ogawa S, Haeno H, Natsume A. Mathematical Modeling and Mutational Analysis Reveal Optimal Therapy to Prevent Malignant Transformation in Grade II IDH-Mutant Gliomas. Cancer research, 81:4861-4873, 2021
2. Fujii Y, Sato Y, Suzuki H, Kakiuchi N, Yoshizato T, Lenis AT, Maekawa S, Yokoyama A, Takeuchi Y, Inoue Y, Ochi Y, Shiozawa Y, Aoki K, Yoshida K, Kataoka K, Nakagawa MM, Nannya Y, Makishima H, Miyakawa J, Kawai T, Morikawa T, Shiraishi Y, Chiba K, Tanaka H, Nagae G, Sanada M, Sugihara E, Sato TA, Nakagawa T, Fukayama M, Ushiku T, Aburatani H, Miyano S, Coleman JA, Homma Y, Solit DB, Kume H, Ogawa S. Molecular classification and diagnostics of upper urinary tract urothelial carcinoma. Cancer cell, 39:793-809.e8, 2021