Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism

• Published in: Oncogene Vol. 41; no. 46; pp. 4994 - 5007
• Main Authors: Watanabe, Kentaro, Kimura, Shunsuke, Seki, Masafumi, Isobe, Tomoya, Kubota, Yasuo, Sekiguchi, Masahiro, Sato-Otsubo, Aiko, Hiwatari, Mitsuteru, Kato, Motohiro, Oka, Akira, Koh, Katsuyoshi, Sato, Yusuke, Tanaka, Hiroko, Miyano, Satoru, Kawai, Tomoko, Hata, Kenichiro, Ueno, Hiroo, Nannya, Yasuhito, Suzuki, Hiromichi, Yoshida, Kenichi, Fujii, Yoichi, Nagae, Genta, Aburatani, Hiroyuki, Ogawa, Seishi, Takita, Junko
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.11.2022; Nature Publishing Group UK
• Subjects: Arginine; Arginine - genetics; Arginine - metabolism; Arginine deiminase; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; DNA methylation; DNA Methylation - genetics; Gene Expression Regulation, Neoplastic; Heterozygosity; Humans; Loss of heterozygosity; Metabolism; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma cells; Risk groups; Serine; Serine - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02489-2

Neuroblastomas require novel therapies that are based on the exploitation of their biological mechanism. To address this need, we analyzed the DNA methylation and expression datasets of neuroblastomas, extracted a candidate gene characterizing the aggressive features, and conducted functional studies. Based on the DNA methylation data, we identified a subgroup of neuroblastoma cases with 11q loss of heterozygosity with extremely poor prognosis. PHGDH, a serine metabolism-related gene, was extracted as a candidate with strong expression and characteristic methylation in this subgroup as well as in cases with MYCN amplification. PHGDH inhibition suppressed neuroblastoma cell proliferation in vitro and in vivo, indicating that the inhibition of serine metabolism by PHGDH inhibitors is a therapeutic alternative for neuroblastoma. Inhibiting the arginine metabolism, which is closely related to serine metabolism using arginine deiminase, had a combination effect both in vitro and in vivo, especially on extracellular arginine-dependent neuroblastoma cells with ASS1 deficiency. Expression and metabolome analyses of post-dose cells confirmed the synergistic effects of treatments targeting serine and arginine indicated that xCT inhibitors that inhibit cystine uptake could be candidates for further combinatorial treatment. Our results highlight the rational therapeutic strategy of targeting serine/arginine metabolism for intractable neuroblastoma.