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To address the role of PI3K\/Akt\/mTOR, we used a novel approach to study mesothelioma ex vivo as tumor fragment spheroids. Freshly resected mesothelioma tissue from 15 different patients was grown in vitro as 1- to 2-mm-diameter fragments, exposed to apoptotic agents for 48 hours with or without PI3K\/Akt\/mTOR inhibitors, and doubly stained for cytokeratin and cleaved caspase 3 to identify apoptotic mesothelioma cells. Mesothelioma cells within the tumor spheroids exhibited striking resistance to apoptotic agents such as TRAIL plus gemcitabine that were highly effective against monolayers. In a majority of tumors (67%; 10 of 15), apoptotic resistance could be reduced by more than 50% by rapamycin, an mTOR inhibitor, but not by LY294002, a PI3K inhibitor. Responsiveness to rapamycin correlated with staining for the mTOR target, p-S6K, in the original tumor, but not for p-Akt. As confirmation of the role of mTOR, siRNA knockdown of S6K reproduced the effect of rapamycin in three rapamycin-responsive tumors. Finally, in 37 mesotheliomas on tissue microarray, p-S6K correlated only weakly with p-Akt, suggesting the existence of Akt-independent regulation of mTOR. We propose that mTOR mediates survival signals in many mesothelioma tumors. Inhibition of mTOR may provide a nontoxic adjunct to therapy directed against malignant mesothelioma, especially in those with high baseline expression of p-S6K.<\/jats:p>","DOI":"10.1165\/rcmb.2007-0460oc","type":"journal-article","created":{"date-parts":[[2008,5,29]],"date-time":"2008-05-29T21:36:25Z","timestamp":1212096985000},"page":"576-583","source":"Crossref","is-referenced-by-count":55,"title":["mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment Spheroids"],"prefix":"10.1093","volume":"39","author":[{"given":"Shannon M.","family":"Wilson","sequence":"first","affiliation":[{"name":"Lung Biology Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Barbone","sequence":"additional","affiliation":[{"name":"Lung Biology Center"},{"name":"Comprehensive Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Lung Biology Center"},{"name":"Comprehensive Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Jablons","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, and"},{"name":"Department of Surgery, University of California San Francisco, San Francisco, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Bueno","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Sugarbaker","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Pathology"},{"name":"Comprehensive Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin J.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. 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