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A STAT3/integrin axis accelerates pancreatic cancer initiation and progression
Alejandro D Campos1, Ryan M Shepard1, Zachary Ortega1
1Department of Pathology, Moores Cancer Center at the University of California San Diego, La Jolla, San Diego, CA, USA; Department of Pathology, Sanford Consortium for Regenerative Medicine at the University of California San Diego, La Jolla, San Diego, CA, USA.
Cell Reports
|July 23, 2025
Summary
The STAT3 pathway drives pancreatic cancer progression. Researchers identified ITGB3 as a key gene regulated by STAT3, promoting tumor growth and potentially stratifying patients for targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The signal transducer and activator of transcription 3 (STAT3) pathway is crucial in pancreatic ductal adenocarcinoma (PDAC) progression.
- STAT3 coordinates cellular responses to stress and inflammation, significantly impacting tumor development.
Purpose of the Study:
- To identify STAT3-regulated genes involved in PDAC progression and poor survival.
- To elucidate the regulatory mechanisms of STAT3 in PDAC.
- To discover novel therapeutic targets and patient stratification strategies for PDAC.
Main Methods:
- ChIP-sequencing (ChIP-seq) on PDAC cells under hypoxia or oncostatin-M treatment.
- Single-cell transcriptomics to analyze gene expression in stressed PDAC cells.
- Chromatin accessibility assays to study gene regulation.
Main Results:
- Phospho-STAT3 binds to regulatory sites of genes linked to poor survival, with ITGB3 identified as a key driver of PDAC initiation and progression.
- ITGB3 expression is enriched in PDAC cells under oxidative stress from chemotherapy and correlates with STAT3 signaling, hypoxia, and the basal subtype.
- Chromatin accessibility at ITGB3 enhancers modulates STAT3-induced expression, revealing a plastic regulatory mechanism. An 18-gene signature was identified for survival stratification.
Conclusions:
- STAT3-mediated regulation of ITGB3 and other adaptive response genes offers a novel mechanism for PDAC progression.
- The identified 18-gene signature can stratify PDAC patient survival outcomes.
- These findings present opportunities for stratifying PDAC subpopulations for STAT3-targeted therapies.
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