CAFs-secreted fatty acids fuel oral cancer progression via lipid raft formation

Objective

Cancer-associated fibroblasts (CAFs) actively reshape the tumor metabolic landscape by synthesizing and secreting free fatty acids (FFAs) that fuel cancer cells malignancy. FFAs are not only catabolized for energy but also incorporated into plasma membrane structures. However, whether cancer cells exploit CAF-derived FFAs for lipid raft assembly—and if this contributes to oncogenic signaling and malignant behaviors in oral cancer—remains largely unexplored.

Design

Integrated TCGA and scRNA-seq analyses delineated lipid metabolism characteristics in oral squamous cell carcinoma (OSCC). Immunohistochemistry, immunoblotting, FFAs quantification, and immunofluorescence were used to assess OSCC uptake of CAFs-derived FFAs and lipid raft assembly. Transwell, wound healing, and CCK-8 assays evaluated oncological behaviors. Methyl-β-cyclodextrin (MβCD) and immunoblotting were used to investigate PI3K/AKT pathway activation.

Results

Lipogenic enzymes showed gradually increased expression from normal tissue to oral leukoplakia and OSCC. Lipid metabolism reprogramming in CAFs led to abundant FFAs secretion, which enhanced Cav-1 expression and lipid raft formation in OSCC cells. Paracrine FFAs uptake activated PI3K/AKT signaling, promoting proliferation, migration, and invasion. MβCD disrupted lipid rafts and suppressed PI3K/AKT signaling in OSCC cells.

Conclusion

CAFs-derived FFAs promote lipid raft synthesis in OSCC cells, activating PI3K/AKT signaling to drive malignant behaviors. Targeting this CAFs–lipid raft axis may represent a novel therapeutic strategy.