Abstract C023: PTEN/STAT3 pathway in cancer-associated fibroblasts in Pancreatic Cancer

Abstract

Abstract Pancreatic cancer is a devastating disease with a high mortality rate with a five-year survival rate of 12%. Recent studies have shed light on the crucial role of cancer-associated fibroblasts (CAFs) in shaping the tumor microenvironment. Our group demonstrated PTEN loss occurs in CAFs in ~25% of PDAC patient samples, which leads to increased activation of signaling pathways in CAFs, including the STAT3 pathway. Conditional deletion of STAT3 in CAFs in a dual flpO/cre recombinase PDAC model correlated with increased survival, decreased M2-like macrophages and increased T-cell infiltration. In the present study we aimed to test the hypothesis that direct interactions between PTEN and STAT3 in cancer CAFs contributes to an immuno-suppressive tumor microenvironment in pancreatic ductal carcinoma (PDAC). To address this hypothesis, we utilized CAFS isolated from the dual recombinase PDAC model. Proximity ligation assays with these CAFS demonstrated that PTEN-STAT3 are in a complex in the cell cytosol that translocate to the nucleus upon IL6 treatment. This finding was validated by co-immunoprecipitation experiments. ChIP-seq analysis of CAFs with PTEN and pSTAT3/STAT3 antibodies revealed a significant overlap in PTEN and pSTAT3/STAT3 occupation of gene promoters. Integrative analysis of PTEN-STAT3 bound genes with corresponding RNA-seq data revealed that the PTEN/STAT3 complex targets cytokines and ligands that directly affect T-cell function, contributing to an immune suppressive microenvironment. Analysis of human PDAC samples support the relationship between STAT3 activation and T-cell activity. Identifying PTEN/STAT3 targets in CAFs may provide new avenues for overcoming the anti-tumor immune responses in PDAC. Citation Format: Samaneh Saberi, Cameron Bumbleburg, Victoria Jordan, Julia E. Lefler, Sudarshana Sharma, Michael C. Ostrowski. PTEN/STAT3 pathway in cancer-associated fibroblasts in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C023.