Estrogen Production in Pancreatic Cancer Shapes a Tumor Suppressive Stromal Microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death due to a lack of effective therapeutic interventions. PDAC tumors are highly fibrotic, and stromal abundance is hypothesized to contribute to patient outcomes. However, stromal fibroblasts can be tumor-promoting and -restraining, which could explain the disappointing clinical results of stromal targeting therapies. Here, we observed that serum levels of stromal biomarkers associated with favorable outcomes were significantly higher in female PDAC patients compared to male patients. This was supported by in silico estimates of stromal abundance across solid cancers, as well as magnetic resonance elastography and tissue staining which revealed that female PDAC patients had stiffer tumor tissue. Gene expression analysis revealed that estrogen signaling instructs a stromal fibroblast phenotype that is associated with relatively indolent molecular subtypes and a more favorable prognosis, which is maintained by stromal expression of C-type lectin CLEC3B. Remarkably, estrogens were detected intra-tumorally, and pancreatic cancer cells expressed key enzymes for estrogen synthesis. Estrogen production in PDAC was fueled by the catabolism of stroma-derived branched chain amino acids, which ultimately resulted in the production of steroid hormone precursors. Together, these data reveal important hormone-driven factors that limit tumor progression by reprogramming the tumor microenvironment and provide leads for therapy development for PDAC.