WNT 致癌转录需要 MYC 抑制胃肿瘤中的溶酶体活性并稳定 EPCAM。
WNT Oncogenic Transcription Requires MYC Suppression of Lysosomal Activity and EPCAM Stabilization in Gastric Tumours.
发表日期：2024 Jul 04
作者：
Patrizia Mulè, Daniel Fernandez-Perez, Simona Amato, Daria Manganaro, Paola Oldani, Stefania Brandini, Giuseppe Diaferia, Alessandro Cuomo, Camilla Recordati, Chiara Soriani, Ambra Dondi, Marika Zanotti, Samantha Rustichelli, Andrea Bisso, Salvatore Pece, Simona Rodighiero, Gioacchino Natoli, Bruno Amati, Karin Johanna Ferrari, Fulvio Chiacchiera, Diego Pasini
来源：
GASTROENTEROLOGY
摘要：
WNT 信号传导对于空间组织排列至关重要，调节干细胞活性，是胃肠道癌症的标志。虽然 WNT 在驱动肠道肿瘤中的作用已得到充分表征，但 WNT 在胃肿瘤发生中的作用仍然难以捉摸。我们开发了小鼠模型来控制 B-CATENIN 致癌形式的特异性表达，并结合胃窦 Lgr5 细胞中的 MYC 激活。我们使用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。我们报告说，胃中的组成型 B-CATENIN 稳定作用具有可忽略不计的致癌作用，并且需要 MYC 激活来诱导胃肿瘤形成。虽然胃腺中生理上低 MYC 水平限制了 B-CATENIN 转录活性，但 MYC 表达增加会释放 WNT 致癌转录程序，在没有直接转录配合的情况下促进 B-CATENIN 增强子入侵。 MYC 激活会诱导代谢重连，通过 mTOR 和 ERK 激活以及 MiT/TFE 抑制来抑制溶酶体生物合成。这可以防止巨胞饮作用导致 EPCAM 降解，促进 B-CATENIN 染色质积累和 WNT 致癌转录激活。我们的结果揭示了一种新的信号传导框架，对于控制胃上皮结构和 WNT 依赖性致癌转化具有重要意义。版权所有 © 2024 AGA Institute。由爱思唯尔公司出版。保留所有权利。
WNT signaling is central to spatial tissue arrangement, regulating stem cell activity, and represents the hallmark of gastrointestinal cancers. While its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive.We have developed mouse models to control the specific expression of an oncogenic form of B-CATENIN in combination with MYC activation in Lgr5+ cells of the gastric antrum. We used multi-omics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis.We report that constitutive B-CATENIN stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumour formation. While physiologically low MYC levels in gastric glands limit B-CATENIN transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting B-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 B-CATENIN chromatin accumulation and activation of WNT oncogenic transcription.Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.