| First Author | Mulè P | Year | 2024 |
| Journal | Gastroenterology | Volume | 167 |
| Issue | 5 | Pages | 903-918 |
| PubMed ID | 38971196 | Mgi Jnum | J:353458 |
| Mgi Id | MGI:7714333 | Doi | 10.1053/j.gastro.2024.06.029 |
| Citation | Mule P, et al. (2024) WNT Oncogenic Transcription Requires MYC Suppression of Lysosomal Activity and EPCAM Stabilization in Gastric Tumors. Gastroenterology |
| abstractText | 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. METHODS: We have developed mouse models to control the specific expression of an oncogenic form of beta-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. RESULTS: We report that constitutive beta-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 beta-catenin transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting beta-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 beta-catenin chromatin accumulation and activation of WNT oncogenic transcription. CONCLUSION: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation. |
