Deciphering the Opposing Roles of STAT Proteins in Tumor Immune Plasticity and Prognosis in Pancreatic Cancer

• Applicant: Dr. Shiv Singh
• Subject Area: Gastroenterology ; Immunology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569637498

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer, with a 5-year survival rate of less than 12%. Clinically, the primary treatments include gemcitabine combined with nab-paclitaxel and FOLFIRINOX, but therapy resistance and recurrence are major biomedical challenges. Only a small cohort benefits from targeted therapy, leaving majority of patients without effective personalized treatment options. The molecular complexity of PDAC, including heterogeneity within epithelial neoplastic cells and stromal immune compartments, poses both therapeutic challenges and vulnerabilities. Despite advancements in deep molecular profiling, the mechanisms underlying PDAC aggressiveness and its therapeutic vulnerabilities—both intrinsic and extrinsic—remain largely unclear. Our research proposal builds on the premise that cell type-specific inflammatory factors, along with their spatial inflammatory immune microenvironment, influence PDAC plasticity and disease aggressiveness, thereby predicting novel therapeutic vulnerabilities. Our preliminary results show that the STAT1high/STAT3low signaling response correlates with heightened immune inflammation and poor clinical outcomes, while the STAT3high/STAT1low is associated better survival in preclinical models. Notably, longitudinal sampling of matched resected and metastatic PDAC patient specimens revealed an inverse correlation between STAT1 and STAT3 expression. We hypothesize that characterizing both tumor-intrinsic and extrinsic inflammatory networks will enhance our understanding of spatial heterogeneity and uncover new therapeutic vulnerabilities in PDAC. Our study will (i) identify tumor immune modulatory functions through longitudinal sampling; (ii) analyze tumor and inflammatory immune interactions by examining STAT1 and STAT3-associated networks; and (iii) develop new therapeutic strategies by targeting these interactions. We believe that this research proposal will contribute to a deeper understanding of the mechanisms underlying tumor immune networks in PDAC and identify targeted therapeutic options.

• DFG Programme: Research Grants