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

Elisabet Ampudia-Mesias, Charles S. Cameron, Eunjae Yoo, Marcus D Kelly, Sarah M Anderson, Riley Manning, Juan E. Abrahante Lloréns, Christopher L. Moertel, Hyungshin Yim, David J. Odde, Nurten Saydam, Okay Saydam

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4416
JournalInternational journal of molecular sciences
Volume25
Issue number8
DOIs
StatePublished - Apr 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Keywords

  • LMD
  • OTX2
  • group 3 medulloblastoma
  • mTORC2

PubMed: MeSH publication types

  • Journal Article

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