Single-nuclei RNA sequencing reveals obesity-associated rewiring of estrogen signaling in endometrioid adenocarcinoma

Endometrioid adenocarcinoma has one of the strongest body mass index associations of any solid tumor. This is widely attributed to amplification of estrogen-driven signaling via increased production of unopposed estrogen in peripheral adipose tissue. However, there is little evidence as to whether this is a pure dosage effect or if persistent signaling leads to feedback on the execution of that signaling. Using single-nucleus RNA sequencing of primary tumors from postmenopausal patients with normal and obese body mass indices, we identified coordinated transcriptional remodeling across tumor epithelial, immune, and stromal compartments. Network-level analysis of tumor epithelial cells revealed that ESR1-associated co-expression modules in tumors from patients with obesity were distinct across two independent patient cohorts and transcriptomic modalities. These network constructions were then shown to be enriched for estrogen receptor targets using existing chromatin immunoprecipitation data from endometrioid adenocarcinoma cell lines and normal endometrial tissue, as well as RNA-seq following exogenous exposure to estrogen for the cell lines. Thus, this study provides a single-nuclei atlas of endometrioid adenocarcinoma and suggests that obesity likely both amplifies estrogenic signaling and qualitatively reshapes its regulatory context.