Tissue-specific fibroblast lipid cues impose the rate of epithelial cancer invasion

Squamous cell carcinomas (SCCs) originate in epithelial tissues of older
individuals who have been exposed to environmental carcinogens. Despite
overlapping clinical hallmarks, SCCs from different anatomic sites have
different prognoses.

Here we show that fibroblasts confer site-specific cues that determine SCC proliferation and invasion. Oral and lung fibroblasts  have distinct lipid metabolism, transferring unique lipids to SCC cells that promote epithelial-to-mesenchymal transition, and oral and lung SCC  invasion. Whereas oral fibroblasts transfer sphingomyelins, which activate  the ceramide–sphingosine-1-phosphate–STAT3 pathway and promote oral  SCC invasion, lung fibroblasts transfer triglycerides to lung SCCs, thereby triggering cholesterol synthesis and invasion, which is associated with poor survival.

By contrast, dermal fibroblasts are lipid poor, and cutaneous SCC is less invasive. Our data indicate that targeting fibroblast lipid synthesis and SCC lipid uptake or breakdown inhibits oral and lung epithelial cancer invasion.