Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism

Shunsuke Kimura; Masahiro Sekiguchi; Kentaro Watanabe; Mitsuteru Hiwatarai; Masafumi Seki; Kenichi Yoshida; Tomoya Isobe; Yusuke Shiozawa; Hiromichi Suzuki; Noriko Hoshino; Yasuhide Hayashi; Akira Oka; Satoru Miyano; Seishi Ogawa; Junko Takita

doi:10.1371/journal.pone.0245526

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism

PLoS One. 2021 Jan 19;16(1):e0245526. doi: 10.1371/journal.pone.0245526. eCollection 2021.

Authors

Shunsuke Kimura^{1

2}, Masahiro Sekiguchi¹, Kentaro Watanabe¹, Mitsuteru Hiwatarai¹, Masafumi Seki¹, Kenichi Yoshida³, Tomoya Isobe¹, Yusuke Shiozawa³, Hiromichi Suzuki³, Noriko Hoshino¹, Yasuhide Hayashi⁴, Akira Oka¹, Satoru Miyano⁵, Seishi Ogawa³, Junko Takita^{1

6}

Affiliations

¹ Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Pediatrics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
³ Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴ Institute of Physiology and Medicine, Jobu University, Gunma, Japan.
⁵ Human Genome Center Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁶ Department of Pediatrics, Kyoto University, Kyoto, Japan.

Abstract

Neuroblastoma, the most common extracranial solid malignancy among children, originates from undifferentiated neural crest cells (NCC). Despite recent intensified treatment, high-risk patients still have a high mortality rate. To explore a new therapeutic strategy, we performed an integrated genomic and transcriptomic analysis of 30 high-risk neuroblastoma cases. Based on the expression profiling of RNA sequencing, neuroblastoma was classified into Mesenchymal (MES; n = 5) and Noradrenergic (ADRN; n = 25) clusters, as previously reported in the super-enhancer landscape. The expression patterns in MES-cluster cases were similar to normal adrenal glands, with enrichment in secretion-related pathways, suggesting chromaffin cell-like features built from NCC-derived Schwann cell precursors (SCPs). In contrast, neuron-related pathways were enriched in the ADRN-cluster, indicating sympathoblast features reported to originate from NCC but not via SCPs. Thus, MES- and ADRN-clusters were assumed to be corresponding to differentiation pathways through SCP and sympathoblast, respectively. ADRN-cluster cases were further classified into MYCN- and ATRX-clusters, characterized by genetic alterations, MYCN amplifications and ATRX alterations, respectively. MYCN-cluster cases showed high expression of ALDH18A1, encoding P5CS related to proline production. As reported in other cancers, this might cause reprogramming of proline metabolism leading to tumor specific proline vulnerability candidate for a target therapy of metabolic pathway. In ATRX-cluster, SLC18A2 (VMAT2), an enzyme known to prevent cell toxicity due to the oxidation of dopamine, was highly expressed and VMAT2 inhibitor (GZ-793A) represented significant attenuation of cell growth in NB-69 cell line (high SLC18A2 expression, no MYCN amplification) but not in IMR-32 cell line (MYCN amplification). In addition, the correlation of VMAT2 expression with metaiodobenzylguanidine (MIBG) avidity suggested a combination of VMAT2 inhibitor and MIBG radiation for a novel potential therapeutic strategy in ATRX-cluster cases. Thus, targeting the characteristics of unique neuroblastomas may prospectively improve prognosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cluster Analysis
Gene Dosage
Gene Expression Profiling*
Genetic Predisposition to Disease / genetics*
Humans
Mutation
Neuroblastoma / genetics
Neuroblastoma / metabolism*
Neuroblastoma / pathology*

Grants and funding

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI; grant nos. JP20H00528 to J.T. and JP26221308 and JP19H05656 to S.O.); Project for Cancer Research and Therapeutic Evolution (P-CREATE; grant no. JP18cm0106509h9903 and JP19cm0106509h9904 to J.T.), Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT; grant no. JP20cm0106501h0005 to S.O.), and Practical Research for Innovative Cancer Control (grant no. JP19ck0106468h0001 to J.T.) from Japan Agency for Medical Research and Development (AMED) and Princess Takamatsu Cancer Research Fund (grant to J.T.). The other authors received no specific funding for this work.