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Left\u2010right determination factor (LEFTY) and Nodal, members of the transforming growth factor \u03b2 (TGF\u2010\u03b2) superfamily, have glycogen synthase kinase 3\u03b2 (GSK\u20103\u03b2) phosphorylation motifs and are linked with stemness in human malignancies. Herein, we investigated the roles of LEFTY and Nodal in GBM hypoxic foci. In clinical samples, significantly higher expression of LEFTY, Nodal, phospho (p) GSK\u20103\u03b2, pSmad2, and Nestin, as well as higher apoptotic and lower proliferation rates, were observed in nonpseudopalisading (non\u2010Ps) perinecrotic lesions as compared to Ps and non\u2010necrotic tumor lesions, with a positive correlation between LEFTY, Nodal, pGSK\u20103\u03b2, or pSmad2 scores. In KS\u20101, a GBM cell line that lacks endogenous Nodal expression, treatment with the hypoxic mimetic CoCl<jats:sub>2<\/jats:sub> increased LEFTY, pGSK\u20103\u03b2, and pSmad2 levels, but decreased pAkt levels. Moreover, the promoter for <jats:italic>LEFTY<\/jats:italic>, but not <jats:italic>Nodal<\/jats:italic>, was activated by Smad2 or TGF\u2010\u03b21, suggesting that overexpression of LEFTY and Nodal may be due to Akt\u2010independent GSK\u20103\u03b2 inactivation, with or without cooperation of the TGF\u2010\u03b21\/Smad2 axis. LEFTY and Nodal overexpression increased proliferation rates and reduced susceptibility to CoCl<jats:sub>2<\/jats:sub>\u2010induced apoptosis, and increased the expression of epithelial\u2010mesenchymal transition (EMT)\/GSC\u2010related markers. An increased ALDH1<jats:sup>high<\/jats:sup> population and more efficient spheroid formation was also observed in LEFTY\u2010overexpressing cells. These findings suggest that LEFTY and Nodal may contribute to cell survival in non\u2010Ps GBM perinecrotic lesions, leading to alterations in apoptosis, proliferation, or EMT\/GCS features.<\/jats:p>","DOI":"10.1002\/mc.23265","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T10:46:32Z","timestamp":1603881992000},"page":"1409-1419","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Requirements of LEFTY and Nodal overexpression for tumor cell survival under hypoxia in glioblastoma"],"prefix":"10.1002","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9767-317X","authenticated-orcid":false,"given":"Toshihide","family":"Matsumoto","sequence":"first","affiliation":[{"name":"Department of Pathology Kitasato University School of Medicine  Kanagawa 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