Spatially Resolved Obesity-Driven Molecular Changes in Early Breast Cancer

Abstract

Obesity is an established risk factor for invasive breast ductal carcinoma (IDC); however, the specific molecular heterogeneity distinguishing IDC from ductal carcinoma in situ (DCIS) within the obese tumor microenvironment is not well defined. In the current study, spatially resolved transcriptomics was used to profile the epithelial, stromal, and immune compartments of DCIS and IDC lesions stratified by host body mass index, categorized as non-obese (≤29.9 kg/m²) or obese (≥30 kg/m²). These analyses reveal that the transcriptional signatures defining the invasive state differ significantly across body mass index categories. In non-obese patients, IDC lesions exhibited canonical profiles driven by proliferation and epithelial-to-mesenchymal transition, compared with DCIS. Conversely, the obese setting was characterized by a distinct stress-adaptive phenotype, enriched for metabolic adjustment, oxidative stress response, and inflammatory signaling. The epithelial component was accompanied by a fibro-inflammatory stromal signature and an immunosuppressive niche characterized by B-cell depletion and M2 macrophage enrichment. Furthermore, sulfatase 2 (SULF2), an extracellular endosulfatase involved in extracellular matrix organization and signaling, was consistently up-regulated within the obese epithelium, providing a plausible link between metabolic stress and structural remodeling. Collectively, these data indicate obesity-associated differences consistent with an alternative invasive transcriptional program that is less dominated by classical proliferative drivers in this cohort. Consequently, standard prognostic markers may be context dependent, highlighting the need to integrate metabolic health into precision risk stratification.