A histone methylation-MAPK signaling axis drives durable epithelial-mesenchymal transition in hypoxic pancreatic cancer
Brown, Brooke A; Myers, Paul J; Adair, Sara J; Pitarresi, Jason R; Sah-Teli, Shiv K; Campbell, Logan A; Hart, William S; Barbeau, Michelle C; Leong, Kelsey; Seyler, Nicholas; Kane, William; Lee, Kyoung Eun; Stelow, Edward; Jones, Marieke; Simon, M Celeste; Koivunen, Peppi; Bauer, Todd W; Stanger, Ben Z; Lazzara, Matthew J (2024-06-04)
Avaa tiedosto
Sisältö avataan julkiseksi: 04.06.2025
Waverly Press
04.06.2024
Brooke A. Brown, Paul J. Myers, Sara J. Adair, Jason R. Pitarresi, Shiv K. Sah-Teli, Logan A. Campbell, William S. Hart, Michelle C. Barbeau, Kelsey Leong, Nicholas Seyler, William Kane, Kyoung Eun Lee, Edward Stelow, Marieke Jones, M. Celeste Simon, Peppi Koivunen, Todd W. Bauer, Ben Z. Stanger, Matthew J. Lazzara; A Histone Methylation–MAPK Signaling Axis Drives Durable Epithelial–Mesenchymal Transition in Hypoxic Pancreatic Cancer. Cancer Res 1 June 2024; 84 (11): 1764–1780. https://doi.org/10.1158/0008-5472.CAN-22-2945
https://rightsstatements.org/vocab/InC/1.0/
© 2024 American Association for Cancer Research.
https://rightsstatements.org/vocab/InC/1.0/
© 2024 American Association for Cancer Research.
https://rightsstatements.org/vocab/InC/1.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202504282943
https://urn.fi/URN:NBN:fi:oulu-202504282943
Tiivistelmä
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.
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.
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