Annual Report 2024
Division of Brain Tumor Translational Research
Hiromichi Suzuki, Takayuki Nomura, Shiho Iwasaki, Morita Yoko, Takuma Nakashima, Yuriko Sugihara, Mai Kitahara, Tsubasa Miyauchi
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 enable highly accurate and low-cost diagnosis of brain tumors based on molecular classification.
We provide bioinformatics analyses for other cancer genome projects, especially for urological cancers and retinoblastomas.
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 multi-omics sequencing 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. We are also developing long-read sequencing analysis for brain tumors.
2. Genetic analysis of medulloblastoma
We demonstrated the close relationship between genetic abnormalities and normal brain development of which failure leads to medulloblastoma tumorigenesis. We reported that mutations in the CBFA complex inhibit the normal differentiation of neuronal precursor cells, leading to cellular retention and serving as the origin of medulloblastoma development.
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.
4. Understanding Genome and Epigenome Aberrations in Upper Tract Urothelial Carcinoma
We are progressing with the comprehensive analysis of open chromatin regions using ATAC-seq, single-cell multiome analysis, and the integration of genomic abnormalities.
Education
We have trained a post-doctoral researcher and two 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 therapeutic targets underlying brain tumor pathogenesis. We have also developed rapid clinical applications to diagnose brain tumors, which will lead to the better stratification of patients based on molecular features.
List of papers published in 2024
Journal
1. Lee JJY, Tao R, You Z, Haldipur P, Erickson AW, Farooq H, Hendriske LD, Abeysundara N, Richman CM, Wang EY, Das Gupta N, Hadley J, Batts M, Mount CW, Wu X, Rasnitsyn A, Bailey S, Cavalli FMG, Morrissy S, Garzia L, Michealraj KA, Visvanathan A, Fong V, Palotta J, Suarez R, Livingston BG, Liu M, Luu B, Daniels C, Loukides J, Bendel A, French PJ, Kros JM, Korshunov A, Kool M, Chico Ponce de León F, Perezpeña-Diazconti M, Lach B, Singh SK, Leary SES, Cho BK, Kim SK, Wang KC, Lee JY, Tominaga T, Weiss WA, Phillips JJ, Dai S, Zadeh G, Saad AG, Bognár L, Klekner A, Pollack IF, Hamilton RL, Ra YS, Grajkowska WA, Perek-Polnik M, Thompson RC, Kenney AM, Cooper MK, Mack SC, Jabado N, Lupien M, Gallo M, Ramaswamy V, Suva ML, Suzuki H, Millen KJ, Huang LF, Northcott PA, Taylor MD. ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip. Nature genetics, 57:88-102, 2025
2. Yamada M, Keller RR, Gutierrez RL, Cameron D, Suzuki H, Sanghrajka R, Vaynshteyn J, Gerwin J, Maura F, Hooper W, Shah M, Robine N, Demarest P, Bayin NS, Zapater LJ, Reed C, Hébert S, Masilionis I, Chaligne R, Socci ND, Taylor MD, Kleinman CL, Joyner AL, Raju GP, Kentsis A. Childhood cancer mutagenesis caused by transposase-derived PGBD5. Science advances, 10:eadn4649, 2024
3. Shibahara I, Nakashima T, Toyoda M, Inukai M, Matsumoto T, Fujitani K, Tanihata Y, Hide T, Fuse N, Suzuki H, Kumabe T. Evolving driver mutations in adult-onset SHH-medulloblastoma originated from radiological cerebellar abnormality. Journal of neuropathology and experimental neurology, 83:791-794, 2024
4. Visvanathan A, Saulnier O, Chen C, Haldipur P, Orisme W, Delaidelli A, Shin S, Millman J, Bryant A, Abeysundara N, Wu X, Hendrikse LD, Patil V, Bashardanesh Z, Golser J, Livingston BG, Nakashima T, Funakoshi Y, Ong W, Rasnitsyn A, Aldinger KA, Richman CM, Van Ommeren R, Lee JJY, Ly M, Vladoiu MC, Kharas K, Balin P, Erickson AW, Fong V, Zhang J, Suárez RA, Wang H, Huang N, Pallota JG, Douglas T, Haapasalo J, Razavi F, Silvestri E, Sirbu O, Worme S, Kameda-Smith MM, Wu X, Daniels C, MichaelRaj AK, Bhaduri A, Schramek D, Suzuki H, Garzia L, Ahmed N, Kleinman CL, Stein LD, Dirks P, Dunham C, Jabado N, Rich JN, Li W, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Millen KJ, Ellison DW, Dimitrov DS, Taylor MD. Early rhombic lip Protogenin(+ve) stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma. Cell, 187:4733-4750.e26, 2024
5. Iijima K, Fujii H, Suzuki F, Murayama K, Goto YI, Saito Y, Sano T, Suzuki H, Miyata H, Kimura Y, Nakashima T, Suzuki H, Iwasaki M, Sato N. Genotype-relevant neuroimaging features in low-grade epilepsy-associated tumors. Frontiers in neurology, 15:1419104, 2024