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 responding to metastatic colonization remains incomplete. To address this, we aimed to generate a human omentum cell atlas and investigate mechanisms underlying cancer-induced organ transformation.

Single-cell RNAseq was performed on a clinical cohort of 36 omentum tissue samples from patients with benign disease and (pre-) invasive, treatment-naive high-grade serous ovarian cancer. Samples were collected from multiple anatomical regions within the omentum. Marker validation was conducted using an independent bulk RNA-seq cohort with matched proteomics, complemented by flow cytometry and spatially resolved confocal immunofluorescence.

The analysis of >110,000 cells identified 12 cell types and over 50 transcriptionally defined states, with distinct enrichment in benign and metastatic samples. Cells adjacent to tumor nodules were classified as inflammatory, while cells in the tumor core aligned with myofibroblast cancer-associated fibroblasts (CAFs). Cancer-associated mesothelial cells and CAFs shared a gene expression program, including immunosuppressive markers, ECM remodelers, and angiogenic factors. RUNX1 was distinct to trans-differentiating cells, a population enriched in metastases and originating from normal mesothelial and mesenchymal progenitor cells. Moreover, RUNX1 was absent in primary tumors, suggesting a key role in the differentiation of normal omental cells upon metastatic colonization.

Cancer cells orchestrate cell reprogramming through a repertoire of signaling factors affecting both proximal and distal omental tissue. Our cell atlas highlights the cellular and molecular determinants of omentum homeostasis, revealing extensive plasticity and cancer-driven cellular reprogramming.