{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T12:32:14Z","timestamp":1775910734691,"version":"3.50.1"},"reference-count":73,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UMN, Medical School Start-Up","award":["HI19C0748"],"award-info":[{"award-number":["HI19C0748"]}]},{"name":"Korea Health Industry Development Institute (KHIDI)","award":["HI19C0748"],"award-info":[{"award-number":["HI19C0748"]}]},{"name":"Ministry of Health &amp; Welfare, Republic of Korea","award":["HI19C0748"],"award-info":[{"award-number":["HI19C0748"]}]},{"name":"Children\u2019s Cancer Research Fund","award":["HI19C0748"],"award-info":[{"award-number":["HI19C0748"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019s 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\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms25084416","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T08:22:44Z","timestamp":1713342164000},"page":"4416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas"],"prefix":"10.3390","volume":"25","author":[{"given":"Elisabet","family":"Ampudia-Mesias","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles S.","family":"Cameron","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunjae","family":"Yoo","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA"},{"name":"Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, Ansan 15588, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4203-4853","authenticated-orcid":false,"given":"Marcus","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah M.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riley","family":"Manning","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan E.","family":"Abrahante Llor\u00e9ns","sequence":"additional","affiliation":[{"name":"University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5474-588X","authenticated-orcid":false,"given":"Christopher L.","family":"Moertel","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7945-3472","authenticated-orcid":false,"given":"Hyungshin","family":"Yim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, Ansan 15588, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7731-2799","authenticated-orcid":false,"given":"David J.","family":"Odde","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nurten","family":"Saydam","sequence":"additional","affiliation":[{"name":"ExoMed Diagnostic, Minneapolis, MN 55404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Okay","family":"Saydam","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00401-011-0800-8","article-title":"Medulloblastoma: Clinicopathological correlates of SHH, WNT, and non-SHH\/WNT molecular subgroups","volume":"121","author":"Ellison","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.ccr.2014.02.004","article-title":"Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition","volume":"25","author":"Kool","year":"2014","journal-title":"Cancer 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