Preclinical study reveals that cancer-associated fibroblasts drive perineural invasion via lactate-induced histone lactylation in pancreatic cancer, highlighting novel therapeutic targets.
Key Points
To determine the molecular and metabolic mechanisms by which cancer-associated fibroblasts promote perineural invasion in pancreatic ductal adenocarcinoma.
Isolated perineural invasion-associated cancer-associated fibroblasts (pCAFs) and non-PNI CAFs, characterizing them via single-cell high-throughput sequencing and metabolomics.
Investigated metabolic flux, GAPDH acetylation, and downstream histone H3K18 lactylation-mediated transcriptional activation of neural invasion genes in cancer cells.
Evaluated the therapeutic inhibition of GAPDH and lactylation in a genetically engineered mouse model and correlated H3K18 lactylation levels with patient prognosis.
pCAFs exhibited marked GAPDH acetylation and elevated glycolytic flux, establishing a high-lactate tumor microenvironment.
Uptake of pCAF-derived lactate induced histone H3K18 lactylation in tumor cells, activating transcription of neural invasion genes L1CAM and SLIT1.
Targeting GAPDH and lactylation modifications significantly reduced perineural invasion in mice, while high H3K18 lactylation correlated with severe invasion and worse patient survival.