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.

中文翻译：

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mTOR的变构和ATP竞争性抑制剂有效抑制Tsc2 +/-小鼠肾脏中与肿瘤进展相关的上皮-间质转化。

在结节性硬化症（TSC）相关的肿瘤中，TSC基因中的突变导致雷帕霉素复合物1（mTORC1）信号转导途径的机械靶标异常激活。mTORC1信号传导影响许多生物学过程，包括上皮-间质转化（EMT），这被认为可促进各种类型癌症中的肿瘤进展和转移。在这项研究中，我们报告了TSC患者癌症中血管平滑肌脂肪瘤和部分EMT中具有上皮和间充质特征的杂交细胞，并描述了从囊肿到乳头状腺瘤再到Tsc2 +/-小鼠肾脏实体癌的肿瘤进展过程中EMT激活的新模型。 。在与TSC相关的囊肿中，EMT的特征很少发生，但随着病变从乳头状腺瘤发展到实体癌（其中上皮-间充质混合细胞丰富），EMT的特征会增加，这表明存在部分EMT。我们还比较了新型ATP竞争性mTOR抑制剂AZD2014与变构mTOR抑制剂雷帕霉素对EMT和肿瘤负荷的影响。AZD2014和雷帕霉素均能有效抑制肾脏肿瘤的EMT，并有效阻断Tsc2 +/-小鼠的肿瘤进展。这些结果表明，部分EMT是人和小鼠中与TSC相关的肾肿瘤的共同特征，并且在TSC相关的肿瘤进展过程中发生。与EMT相关的信号通路可能代表与TSC基因突变相关的肿瘤的治疗靶标。我们还比较了新型ATP竞争性mTOR抑制剂AZD2014与变构mTOR抑制剂雷帕霉素对EMT和肿瘤负荷的影响。AZD2014和雷帕霉素均能有效抑制肾脏肿瘤的EMT，并有效阻断Tsc2 +/-小鼠的肿瘤进展。这些结果表明，部分EMT是人和小鼠中与TSC相关的肾脏肿瘤的共同特征，并且在TSC相关的肿瘤进展过程中发生。与EMT相关的信号通路可能代表与TSC基因突变相关的肿瘤的治疗靶标。我们还比较了新型ATP竞争性mTOR抑制剂AZD2014与变构mTOR抑制剂雷帕霉素对EMT和肿瘤负荷的影响。AZD2014和雷帕霉素均能有效抑制肾脏肿瘤的EMT，并有效阻断Tsc2 +/-小鼠的肿瘤进展。这些结果表明，部分EMT是人和小鼠中与TSC相关的肾肿瘤的共同特征，并且在TSC相关的肿瘤进展过程中发生。与EMT相关的信号通路可能代表与TSC基因突变相关的肿瘤的治疗靶标。这些结果表明，部分EMT是人和小鼠中与TSC相关的肾肿瘤的共同特征，并且在TSC相关的肿瘤进展过程中发生。与EMT相关的信号通路可能代表与TSC基因突变相关的肿瘤的治疗靶标。这些结果表明，部分EMT是人和小鼠中与TSC相关的肾肿瘤的共同特征，并且在TSC相关的肿瘤进展过程中发生。与EMT相关的信号通路可能代表与TSC基因突变相关的肿瘤的治疗靶标。