Allosteric and ATP-competitive inhibitors of mTOR effectively suppress tumor progression-associated epithelial-mesenchymal transition in the kidneys of Tsc2+/− Mice

Jones, Ashley T., Yang, Jian ORCID: https://orcid.org/0000-0003-2631-4553, Narov, Kalin, Henske, Elizabeth P, Sampson, Julian R. ORCID: https://orcid.org/0000-0002-2902-2348 and Shen, Ming Hong ORCID: https://orcid.org/0000-0002-3891-7231 2019. Allosteric and ATP-competitive inhibitors of mTOR effectively suppress tumor progression-associated epithelial-mesenchymal transition in the kidneys of Tsc2+/− Mice. Neoplasia 21 (8) , pp. 731-739. 10.1016/j.neo.2019.05.003

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Abstract

In tuberous sclerosis (TSC)–associated tumors, mutations in the TSC genes lead to aberrant activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. mTORC1 signaling impacts many biological processes including the epithelial-mesenchymal transition (EMT), which is suggested to promote tumor progression and metastasis in various types of cancer. In this study, we report hybrid cells with epithelial and mesenchymal features in angiomyolipomas and partial EMT in carcinomas from TSC patients and describe a new model of EMT activation during tumor progression from cyst to papillary adenoma to solid carcinoma in the kidneys of Tsc2+/− mice. Features of EMT occurred infrequently in TSC-associated cysts but increased as the lesions progressed through papillary adenoma to solid carcinoma where epithelial-mesenchymal hybrid cells were abundant, indicating partial EMT. We also compared the effects of the novel ATP-competitive mTOR inhibitor AZD2014 with the allosteric mTOR inhibitor rapamycin on EMT and tumor burden. Both AZD2014 and rapamycin potently suppressed EMT of renal tumors and effectively blocked tumor progression in Tsc2+/− mice. These results suggest that partial EMT is a shared feature of TSC-associated renal tumors in humans and mice and occurs during TSC-associated tumor progression. EMT-related signaling pathways may represent therapeutic targets for tumors associated with mutations in the TSC genes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	1522-8002
Date of First Compliant Deposit:	26 June 2019
Date of Acceptance:	3 May 2019
Last Modified:	30 May 2023 19:53
URI:	https://orca.cardiff.ac.uk/id/eprint/123743

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