Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability

• Published in: Nature communications Vol. 14; no. 1; p. 762
• Main Authors: Luo, Zaili, Xin, Dazhuan, Liao, Yunfei, Berry, Kalen, Ogurek, Sean, Zhang, Feng, Zhang, Liguo, Zhao, Chuntao, Rao, Rohit, Dong, Xinran, Li, Hao, Yu, Jianzhong, Lin, Yifeng, Huang, Guoying, Xu, Lingli, Xin, Mei, Nishinakamura, Ryuichi, Yu, Jiyang, Kool, Marcel, Pfister, Stefan M, Roussel, Martine F, Zhou, Wenhao, Weiss, William A, Andreassen, Paul, Lu, Q Richard
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.02.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Ablation; Amplification; Animals; Brain Neoplasms; Brain tumors; Cell Transformation, Neoplastic - genetics; Cerebellar Neoplasms - pathology; Cerebellum; Child; Children; Chromosomes; Genetic transformation; Genomic Instability; Humans; Kinases; Medical prognosis; Medulloblastoma; Medulloblastoma - pathology; Mice; Mutation; Myc protein; p53 Protein; Phosphatase; Phosphoprotein Phosphatases - genetics; Phosphoric Monoester Hydrolases - genetics; Phosphorylation; Post-translation; Prognosis; Proto-Oncogene Proteins c-myc - genetics; Stability; Tumor suppressor genes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36400-8

MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.