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Published on: July 28, 2010
Multi-omic profiling reveals SMAD4 drives linoleic acid-arachidonic acid metabolism to mediate PDAC radiosensitivity
Yang Wang1, Shan Zhang2, Yiran Song3
1Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; JiangWan Hospital of Hongkou District, Shanghai University of Medicine and Health Sciences, Shanghai, 200083, China.
Background:
Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent SMAD4 inactivation and extensive lipid metabolic rewiring, yet the mechanistic crosstalk between these processes remains poorly elucidated.
Methods:
Multi-omic profiling involving CUT&Tag, transcriptomic, and spatial metabolomic analyses reveals a novel regulatory mechanism of arachidonic acid metabolism governed by SMAD4 that determines PDAC radioresistance.
Results:
Spatial metabolomics revealed that SMAD4 deficiency decreases arachidonic acid metabolism in PDAC tissues. Mechanistically, SMAD4 binds to the promoters of SLC27A3 and FADS2, facilitating the enrichment of the linoleic acid-arachidonic acid axis. Conversely, SMAD4 deficiency leads to a decrease in the linoleic acid-arachidonic acid axis, which may inhibit ferroptosis and promote radioresistance in PDAC tumors.
Conclusions:
Collectively, our study identifies that SMAD4 acts as a transcriptional activator of SLC27A3 and FADS2, driving linoleic acid uptake and its conversion to arachidonic acid, which may subsequently trigger ferroptosis and enhance radiosensitivity.
Insights
SMAD4 inactivation in pancreatic cancer alters arachidonic acid metabolism, impacting ferroptosis and radioresistance. Restoring this pathway may enhance treatment sensitivity.
Area of Science:
- Oncology
- Metabolomics
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) frequently exhibits SMAD4 inactivation.
- Significant lipid metabolic alterations are observed in PDAC.
- The interplay between SMAD4 and lipid metabolism in PDAC is not well understood.
Purpose of the Study:
- To elucidate the mechanistic link between SMAD4 and lipid metabolism in PDAC.
- To investigate the role of SMAD4 in regulating arachidonic acid metabolism.
- To determine the impact of this regulation on PDAC radioresistance.
Main Methods:
- Multi-omic profiling including CUT&Tag, transcriptomics, and spatial metabolomics.
- Analysis of SMAD4 binding to gene promoters.
- Assessment of arachidonic acid metabolism and ferroptosis markers.
Main Results:
- SMAD4 deficiency reduces arachidonic acid metabolism in PDAC.
- SMAD4 directly regulates SLC27A3 and FADS2 gene expression.
- Reduced arachidonic acid metabolism due to SMAD4 loss may promote radioresistance by inhibiting ferroptosis.
Conclusions:
- SMAD4 functions as a transcriptional activator for SLC27A3 and FADS2.
- SMAD4 promotes linoleic acid uptake and conversion to arachidonic acid.
- This pathway, influenced by SMAD4, is critical for ferroptosis induction and radiosensitivity in PDAC.
