Abstract：
OBJECTIVE: WNT signaling is central to spatial tissue arrangement and regulating stem cell activity, and it represents the hallmark of gastrointestinal cancers. Although its role in driving intestinal tumors is well characterized, WNT\'s role in gastric tumorigenesis remains elusive.
METHODS: We have developed mouse models to control the specific expression of an oncogenic form of β-catenin in combination with MYC activation in Lgr5+ cells of the gastric antrum. We used multiomics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis.
RESULTS: We report that constitutive β-catenin stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumor formation. Although physiologically low MYC levels in gastric glands limit β-catenin transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting β-catenin enhancer invasion without a direct transcriptional cooperation. MYC activation induces a metabolic rewiring that suppresses lysosomal biogenesis through mTOR and ERK activation and MiT/TFE inhibition. This prevents EPCAM degradation by macropinocytosis, promoting β-catenin chromatin accumulation and activation of WNT oncogenic transcription.
CONCLUSIONS: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.
METHODS: We have developed mouse models to control the specific expression of an oncogenic form of β-catenin in combination with MYC activation in Lgr5+ cells of the gastric antrum. We used multiomics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis.
RESULTS: We report that constitutive β-catenin stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumor formation. Although physiologically low MYC levels in gastric glands limit β-catenin transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting β-catenin enhancer invasion without a direct transcriptional cooperation. MYC activation induces a metabolic rewiring that suppresses lysosomal biogenesis through mTOR and ERK activation and MiT/TFE inhibition. This prevents EPCAM degradation by macropinocytosis, promoting β-catenin chromatin accumulation and activation of WNT oncogenic transcription.
CONCLUSIONS: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.
摘要：
目的：WNT信号传导是空间组织排列的核心，调节干细胞活性，并代表胃肠道癌症的标志。虽然它在驱动肠道肿瘤中的作用是很好的特征，WNT在胃癌发生中的作用仍然难以捉摸。
方法：我们开发了小鼠模型来控制B-CATENIN致癌形式的特异性表达，并结合MYC在胃窦的Lgr5+细胞中的激活。我们使用在体内和类器官模型中应用的多组学方法来表征它们在驱动胃肿瘤发生中的合作。
结果：我们报道了胃中的组成型B-CATENIN稳定具有可忽略的致癌作用，并且需要激活MYC来诱导胃肿瘤形成。虽然胃腺中生理上较低的MYC水平限制了B-CATENIN转录活性，MYC表达的增加释放了WNT致癌转录程序，在没有直接转录合作的情况下促进B-CATENIN增强子入侵。MYC活化通过mTOR和ERK活化以及MiT/TFE抑制诱导抑制溶酶体生物发生的代谢重组。这可以防止EPCAM通过巨噬细胞增多而降解，促进B-CATENIN染色质积累和WNT致癌转录的激活。
结论：我们的结果揭示了一个新的信号传导框架，对控制胃上皮结构和WNT依赖性致癌转化具有重要意义。
方法：我们开发了小鼠模型来控制B-CATENIN致癌形式的特异性表达，并结合MYC在胃窦的Lgr5+细胞中的激活。我们使用在体内和类器官模型中应用的多组学方法来表征它们在驱动胃肿瘤发生中的合作。
结果：我们报道了胃中的组成型B-CATENIN稳定具有可忽略的致癌作用，并且需要激活MYC来诱导胃肿瘤形成。虽然胃腺中生理上较低的MYC水平限制了B-CATENIN转录活性，MYC表达的增加释放了WNT致癌转录程序，在没有直接转录合作的情况下促进B-CATENIN增强子入侵。MYC活化通过mTOR和ERK活化以及MiT/TFE抑制诱导抑制溶酶体生物发生的代谢重组。这可以防止EPCAM通过巨噬细胞增多而降解，促进B-CATENIN染色质积累和WNT致癌转录的激活。
结论：我们的结果揭示了一个新的信号传导框架，对控制胃上皮结构和WNT依赖性致癌转化具有重要意义。
