Deconvolved tumor adipocyte proportions and high grade serous ovarian carcinoma survival

Abstract

BackgroundSingle-cell-based analyses of high-grade serous ovarian carcinoma (HGSOC) survival have largely ignored adipocytes, which are fragile and under-represented in single-cell references. Adipocytes are known active components of the tumor microenvironment in many cancers, and HGSOC tumors frequently metastasize to the omentum, a lining of adipose tissue. MethodsWe created a composite reference that combines single-nucleus adipose profiles with published HGSOC single-cell data to deconvolve 588 bulk RNA-seq tumours from the Schildkraut cohorts. We used stage-stratified Cox models to quantify the association between intratumoural adipocyte fractions and overall survival while adjusting for age, body mass index (BMI), race, and residual disease. We also evaluated associations with deconvolved immune, stromal, and epithelial cell groups. ResultsA 10% increase in estimated tumor adipocyte content was associated with a 41% increase in the hazard of death (HR = 1.41, 95% CI 1.18-1.70, p = 0.0002) after adjusting for age, BMI and race (n=566). A 10% increase in immune cell proportion was associated with favorable survival (HR = 0.82, 95% CI 0.69-0.97, p = 0.024). Stromal and epithelial macro-fractions were not associated with survival. Associations with adipocyte and immune cell type proportions were unchanged in models additionally controlling the other cell type proportions. Results were similar after additionally adjusting for residual disease after debulking surgery. ConclusionsAdipocytes may be a tumor-intrinsic factor associated with adverse outcomes in HGSOC. Quantifying adipocyte burden using bulk RNA-seq could enhance risk stratification and guide the development of adipocyte-targeted therapies.