P-168 Estrogen signaling shapes a tumor suppressive stroma in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis. A major hurdle to the efficacy of current systemic therapies is the abundance of non-tumor cells and material, known collectively as the stroma, which may both hamper drug delivery and support tumor growth and resistance. However, tumor restraining activities have also been attributed to the stroma which may explain the disappointing results of stroma-targeting in clinical studies so far. We previously identified a novel serum biomarker, Osteoglycin, which identified a subset of cancer-associated fibroblast (CAFs) that distinctly associated with favorable outcomes. Closer inspection showed that OGN serum levels were relatively higher in female patients. This led us to hypothesize that stromal composition may differ between genders, and that this is driven by hormonal cues. Biobanked serum samples were included in this study and analyzed for stromal biomarkers. Subsequently, publicly available bulk and single cell gene expression data, as well as in-house datasets, were interrogated to identify hormone-regulated stromal transcripts and their drivers. This was supported by in vitro experiments to assess the effects of estrogen on CAF phenotype. Further, genetic perturbations were conducted to reveal the impact of estrogen-dependent regulators of CAF phenotype. Meta analyses were performed to associate candidate genes to survival in PDAC, and across cancer types. We found that female gender strongly associated with stromal abundance across many TCGA cancer types, but most notably in PDAC. The association was driven by estrogen signaling and was particularly strong for the previously identified tumor-suppressive inflammatory CAF (iCAF) phenotype. Exposing CAF precursors to β-estradiol indeed resulted in a shift towards the iCAF phenotype. Further examination showed that C-type lectins strongly associated with estrogen-induced CAF phenotypes suggesting them to be key regulators of tumor suppressive stromal characteristics. Our work revealed that the stromal composition is affected by estrogen signaling and may be taken to suggest that the disappointing responses to stroma targeting in the clinic can also be attributed to this previously unrecognized confounder. Current investigations are underway to determine the mechanisms through which C-type lectins shape a tumor-suppressive stroma, how estrogen instructs this, and to assess whether stroma-related variables such as tumor composition and stiffness are indeed different between genders.