Annual Report 2022
Division of Brain Tumor Translational Research
Hiromichi Suzuki, Atsuhito Uneda, Takuma Nakashima, Yusuke Funakoshi, Yuriko Sugihara, Mai Kitahara, Yuki Yomoda, Reiko Ikeda
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.
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.
2. Genetic analysis of medulloblastoma
We demonstrated significant genetic abnormalities in the Core-binding factor alpha (CBFA) complex constituents in medulloblastoma, a malignant pediatric brain tumor. 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 and the integration of genomic abnormalities.
Clinical Trials
The Japan Clinical Oncology Group (JCOG)-Brain Tumor Study Group was organized in 2002 and multi-institutional randomized controlled trials are ongoing. A “Randomized Phase III study for unresectable WHO Grade II astrocytoma with radiotherapy alone or chemoradiotherapy with temozolomide (JCOG1303)”, a Phase III randomized study for grade III gliomas (JCOG1016), and Phase III study for glioblastoma (JCOG1308, JCOG1703 and JCOG1910) are underway. These studies, under the surveillance of the JCOG, aim to set a standard protocol for treating malignant brain tumor patients. Moreover, a proper methodology for performing randomized studies will be established in the field of neuro-oncology.
An investigator-initiated phase II clinical trial of eribulin targeting TERT in patients with recurrent glioblastomas and a phase II study of temozolomide and metformin for newly-diagnosed glioblastoma are also ongoing under AMED grants.
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 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 2022
Journal
1. Funakoshi Y, Sugihara Y, Uneda A, Nakashima T, Suzuki H. Recent advances in the molecular understanding of medulloblastoma. Cancer science, 114:741-749, 2023
2. Omura T, Takahashi M, Ohno M, Miyakita Y, Yanagisawa S, Tamura Y, Kikuchi M, Kawauchi D, Nakano T, Hosoya T, Igaki H, Satomi K, Yoshida A, Sunami K, Hirata M, Shimoi T, Sudo K, Okuma HS, Yonemori K, Suzuki H, Ichimura K, Narita Y. Clinical Application of Comprehensive Genomic Profiling Tests for Diffuse Gliomas. Cancers, 14:2454, 2022
3. Takeuchi Y, Yoshida K, Halik A, Kunitz A, Suzuki H, Kakiuchi N, Shiozawa Y, Yokoyama A, Inoue Y, Hirano T, Yoshizato T, Aoki K, Fujii Y, Nannya Y, Makishima H, Pfitzner BM, Bullinger L, Hirata M, Jinnouchi K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Okamoto T, Haga H, Ogawa S, Damm F. The landscape of genetic aberrations in myxofibrosarcoma. International journal of cancer, 151:565-577, 2022
4. Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, Ong W, Gordon V, Coudière-Morrison L, Mercier AL, Shokouhian M, Suárez RA, Ly M, Borlase S, Scott DS, Vladoiu MC, Farooq H, Sirbu O, Nakashima T, Nambu S, Funakoshi Y, Bahcheli A, Diaz-Mejia JJ, Golser J, Bach K, Phuong-Bao T, Skowron P, Wang EY, Kumar SA, Balin P, Visvanathan A, Lee JJY, Ayoub R, Chen X, Chen X, Mungall KL, Luu B, Bérubé P, Wang YC, Pfister SM, Kim SK, Delattre O, Bourdeaut F, Doz F, Masliah-Planchon J, Grajkowska WA, Loukides J, Dirks P, Fèvre-Montange M, Jouvet A, French PJ, Kros JM, Zitterbart K, Bailey SD, Eberhart CG, Rao AAN, Giannini C, Olson JM, Garami M, Hauser P, Phillips JJ, Ra YS, de Torres C, Mora J, Li KKW, Ng HK, Poon WS, Pollack IF, López-Aguilar E, Gillespie GY, Van Meter TE, Shofuda T, Vibhakar R, Thompson RC, Cooper MK, Rubin JB, Kumabe T, Jung S, Lach B, Iolascon A, Ferrucci V, de Antonellis P, Zollo M, Cinalli G, Robinson S, Stearns DS, Van Meir EG, Porrati P, Finocchiaro G, Massimino M, Carlotti CG, Faria CC, Roussel MF, Boop F, Chan JA, Aldinger KA, Razavi F, Silvestri E, McLendon RE, Thompson EM, Ansari M, Garre ML, Chico F, Eguía P, Pérezpeña M, Morrissy AS, Cavalli FMG, Wu X, Daniels C, Rich JN, Jones SJM, Moore RA, Marra MA, Huang X, Reimand J, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Pugh TJ, Garzia L, Kleinman CL, Stein LD, Jabado N, Malkin D, Ayrault O, Golden JA, Ellison DW, Doble B, Ramaswamy V, Werbowetski-Ogilvie TE, Suzuki H, Millen KJ, Taylor MD. Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature, 609:1021-1028, 2022
5. Watanabe K, Kimura S, Seki M, Isobe T, Kubota Y, Sekiguchi M, Sato-Otsubo A, Hiwatari M, Kato M, Oka A, Koh K, Sato Y, Tanaka H, Miyano S, Kawai T, Hata K, Ueno H, Nannya Y, Suzuki H, Yoshida K, Fujii Y, Nagae G, Aburatani H, Ogawa S, Takita J. Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism. Oncogene, 41:4994-5007, 2022