Artikel ; Online: A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer.
2024 Band 84, Heft 11, Seite(n) 1764–1780
Abstract: The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting ... ...
| Abstract | The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation-MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. Significance: Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited. See related commentary by Wirth and Schneider, p. 1739. |
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| Mesh-Begriff(e) | Epithelial-Mesenchymal Transition ; Humans ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/drug therapy ; Mice ; Histones/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/drug therapy ; Animals ; Methylation ; MAP Kinase Signaling System ; Cell Line, Tumor ; Tumor Microenvironment ; Mice, Nude ; Xenograft Model Antitumor Assays ; Cell Hypoxia ; Tumor Hypoxia ; Hypoxia/metabolism ; F-Box Proteins ; Jumonji Domain-Containing Histone Demethylases | |||||
| Chemische Substanzen | Histones ; KDM2A protein, human (EC 1.14.11.27) ; F-Box Proteins ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) | |||||
| Sprache | Englisch | |||||
| Erscheinungsdatum | 2024-03-12 | |||||
| Erscheinungsland | United States | |||||
| Dokumenttyp | Journal Article | |||||
| ZDB-ID | 1432-1 | |||||
| ISSN | 1538-7445 ; 0008-5472 | |||||
| ISSN (online) | 1538-7445 | |||||
| ISSN | 0008-5472 | |||||
| DOI | 10.1158/0008-5472.CAN-22-2945 | |||||
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| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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