European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Department of Experimental Oncology, Milan, Italy.
University of Milan, Department of Health Sciences, Milan, Italy.
Gastroenterology. 2024 Oct;167(5):903-918. doi: 10.1053/j.gastro.2024.06.029. Epub 2024 Jul 5.
BACKGROUND & AIMS: 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.
We have developed mouse models to control the specific expression of an oncogenic form of β-catenin (CTNNB1) 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.
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.
Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.
WNT 信号通路对空间组织和干细胞活性的调节至关重要，是胃肠道癌症的标志。虽然其在驱动肠道肿瘤中的作用已得到充分证实，但 WNT 在胃肿瘤发生中的作用仍不清楚。
我们构建了小鼠模型，以控制β-连环蛋白（CTNNB1）的致癌形式与胃窦部 Lgr5 细胞中 MYC 激活的特异性表达。我们采用多组学方法，在体内和类器官模型中对其协同驱动胃肿瘤发生的作用进行了研究。
我们报告称，胃中稳定的β-连环蛋白具有微不足道的致癌作用，并且需要 MYC 激活才能诱导胃肿瘤形成。尽管胃腺中生理水平的 MYC 限制了β-连环蛋白的转录活性，但 MYC 表达的增加会释放 WNT 致癌转录程序，促进β-连环蛋白增强子的入侵，而不会直接进行转录合作。MYC 激活诱导代谢重编程，通过 mTOR 和 ERK 激活以及 MiT/TFE 抑制抑制溶酶体生物发生。这阻止了 EPCAM 通过巨胞饮作用降解，促进β-连环蛋白染色质积累和 WNT 致癌转录的激活。
我们的研究结果揭示了一个新的信号框架，对控制胃上皮结构和 WNT 依赖性致癌转化具有重要意义。
