Ovarian cancer metastasis to the human omentum disrupts organ homeostasis and induces fundamental tissue reprogramming.

The omentum, a visceral adipose tissue with critical metabolic, immunological, and stem cell functions is the preferred site for ovarian cancer metastasis. However, its role in maintaining homeostasis and its responses to metastatic colonization remain incompletely understood. Using single-cell transcriptomics, we profile different anatomical regions of the omentum in patients with benign conditions and metastasis. We catalog the benign omentum and observe a stable cell type composition and a preserved stem and progenitor niche. Upon metastatic colonization, we report on increased immune heterogeneity and a concomitant reduction of mesothelial and progenitor cells. The lesser omentum, which is not routinely removed during surgical debulking, is identified as a premetastatic niche characterized by neutrophil infiltration, extracellular trap formation, and the presence of micrometastases. At established metastatic sites, resident cells exhibit cancer-associated phenotypes with regulatory, anti-adipogenic, and immunosuppressive properties. Cellular reprogramming across the omentum is associated with signaling profiles of tumor cells, suggesting potential influences on both proximal and distal tissue regions. This cell atlas illuminates the cellular and molecular determinants of organ homeostasis and reveals a high degree of plasticity and cellular reprogramming promoted by cancer colonization.