The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas

Int J Mol Sci. 2024 Apr 17;25(8):4416. doi: 10.3390/ijms25084416.

Abstract

Medulloblastoma (MB) encompasses diverse subgroups, and leptomeningeal disease/metastasis (LMD) plays a substantial role in associated fatalities. Despite extensive exploration of canonical genes in MB, the molecular mechanisms underlying LMD and the involvement of the orthodenticle homeobox 2 (OTX2) gene, a key driver in aggressive MB Group 3, remain insufficiently understood. Recognizing OTX2's pivotal role, we investigated its potential as a catalyst for aggressive cellular behaviors, including migration, invasion, and metastasis. OTX2 overexpression heightened cell growth, motility, and polarization in Group 3 MB cells. Orthotopic implantation of OTX2-overexpressing cells in mice led to reduced median survival, accompanied by the development of spinal cord and brain metastases. Mechanistically, OTX2 acted as a transcriptional activator of the Mechanistic Target of Rapamycin (mTOR) gene's promoter and the mTORC2 signaling pathway, correlating with upregulated downstream genes that orchestrate cell motility and migration. Knockdown of mTOR mRNA mitigated OTX2-mediated enhancements in cell motility and polarization. Analysis of human MB tumor samples (N = 952) revealed a positive correlation between OTX2 and mTOR mRNA expression, emphasizing the clinical significance of OTX2's role in the mTORC2 pathway. Our results reveal that OTX2 governs the mTORC2 signaling pathway, instigating LMD in Group 3 MBs and offering insights into potential therapeutic avenues through mTORC2 inhibition.

Keywords: LMD; OTX2; group 3 medulloblastoma; mTORC2.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement* / genetics
  • Cell Proliferation* / genetics
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / metabolism
  • Cerebellar Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 2* / genetics
  • Mechanistic Target of Rapamycin Complex 2* / metabolism
  • Medulloblastoma* / genetics
  • Medulloblastoma* / metabolism
  • Medulloblastoma* / pathology
  • Meningeal Neoplasms* / genetics
  • Meningeal Neoplasms* / metabolism
  • Meningeal Neoplasms* / pathology
  • Meningeal Neoplasms* / secondary
  • Mice
  • Otx Transcription Factors* / genetics
  • Otx Transcription Factors* / metabolism
  • Signal Transduction*

Substances

  • Otx Transcription Factors
  • OTX2 protein, human
  • Mechanistic Target of Rapamycin Complex 2

Grants and funding

This work was supported, in part, by UMN, Medical School Start-Up (O.S.), and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0748, E.Y.), and by the Children’s Cancer Research Fund (O.S., E.A.-M., C.S.C. and C.L.M.), and by U54—U54CA210190 (D.J.O.), P01—P01CA254849 (D.J.O.), U54—U54CA268069 (D.J.O.). This work was also supported by the resources and staff at the University of Minnesota University Imaging Centers (UIC). SCR_020997.