Back to Search
Start Over
WNT Oncogenic Transcription Requires MYC Suppression of Lysosomal Activity and EPCAM Stabilization in Gastric Tumors.
- Source :
-
Gastroenterology [Gastroenterology] 2024 Oct; Vol. 167 (5), pp. 903-918. Date of Electronic Publication: 2024 Jul 05. - Publication Year :
- 2024
-
Abstract
- 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.<br />Methods: 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 <superscript>+</superscript> cells of the gastric antrum. We used multiomics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis.<br />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.<br />Conclusion: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Female
Humans
Male
Mice
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic pathology
Gastric Mucosa metabolism
Gastric Mucosa pathology
Gene Expression Regulation, Neoplastic
Mice, Transgenic
Organoids metabolism
Protein Stability
TOR Serine-Threonine Kinases metabolism
Transcription, Genetic
beta Catenin metabolism
beta Catenin genetics
Epithelial Cell Adhesion Molecule metabolism
Epithelial Cell Adhesion Molecule genetics
Lysosomes metabolism
Proto-Oncogene Proteins c-myc metabolism
Proto-Oncogene Proteins c-myc genetics
Stomach Neoplasms pathology
Stomach Neoplasms metabolism
Stomach Neoplasms genetics
Wnt Signaling Pathway
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 167
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 38971196
- Full Text :
- https://doi.org/10.1053/j.gastro.2024.06.029