Squamous cell carcinoma (SCC) originates in the epithelial tissues of older individuals who have been exposed to environmental carcinogens for a long time. Although SCC from different anatomical sites shares similar clinical features, their prognosis can differ. This study shows that fibroblasts can provide site-specific signals that regulate the proliferation and invasiveness of SCC. Oral and lung fibroblasts have different lipid metabolism traits and can transfer specific lipids to SCC cells, promoting epithelial-mesenchymal transition and invasiveness in oral and lung SCC. Specifically, oral fibroblasts transfer sphingolipids, which activate the ceramide–sphingosine-1-phosphate–STAT3 signaling pathway, promoting oral SCC invasion; while lung fibroblasts transfer triglycerides to lung SCC, triggering cholesterol synthesis and invasion, which is linked to lower patient survival. In contrast, dermal fibroblasts have lower lipid content, and skin SCC tends to be less invasive. Our data suggest that targeting lipid synthesis in fibroblasts or lipid uptake and breakdown in SCC cells could inhibit the invasiveness of oral and lung epithelial cancers.

Reference Information

Nature Metabolism (IF 27.5)

Pub Date: 2026-04-04

DOI: 10.1038/s42255-026-01514-y

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