ArticleCancer research2025
Cancer-Associated Fibroblasts Foster a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed.
- RNA N4-acetylcytidine modification in health and cancer: molecular mechanisms, cellular plasticity, and therapeutic opportunities.Biomarker research · 2026Review
- Review
- Heterogeneity in cancer: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Lactate-Mediated Lysine Lactylation in Renal Fibrosis: Current Progress and Challenges.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Lactylation Remodels Tumorigenesis, Immune Microenvironment, and Therapeutic Response.Current issues in molecular biology · 2026Review
- Neuroimmune interactions: from molecular mechanisms to therapeutic targets.Molecular biomedicine · 2026Review
- Targeting the nervous system: Mechanistic insights into neuro-tumor communication and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- KSTITCH links cellular morphology and gene expression in spatial transcriptomics.bioRxiv : the preprint server for biology · 2026Article
- The tumor microenvironment in pancreatic cancer: from composition to therapeutic targeting.Biochemical Society transactions · 2026Review
- Mitophagy-Competent Cancer-Associated Fibroblasts Fuel Chemoresistance by Rewiring Pyrimidine Metabolism in Pancreatic Cancer.Cancer research · 2026Article
- Neural regulation of cancer: from microenvironmental hijacking to systemic circuit co-option.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Article
- Bioengineered systems to exploit tumor microenvironment metabolism.Trends in cancer · 2026Review
- Carbohydrates metabolic reprogramming and tumor microenvironment in pancreatic cancer: targeting pathways.Molecular biology reports · 2026Review
- Redox Homeostasis, Metabolic Pathways and Plasticity in Uveal Melanoma Compared to Other Cancers.Cancers · 2026Review
- Stromal Regulation of Tumor Perineural Invasion: A Multicellular and Neuro-Ecological Perspective.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Cancer-Associated Fibroblast-Derived Sphingosine-1-Phosphate Activates a MALL-SDC4 Axis to Facilitate Perineural Invasion in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lysine lactylation-mediated post-translational modification: Molecular mechanisms and therapeutic target exploration in tumour drug resistance.Clinical and translational medicine · 2026Review
- Integrins as key regulators in tumor perineural invasion: mechanisms and clinical implications.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Lactate-Induced ZMYM2 K529 Lactylation Stabilizes ZMYM2 and Promotes Platinum Resistance in Ovarian Cancer.International journal of molecular sciences · 2026Article
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14 authors.
Funding
Abstract
Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer, associated with aggressive tumor behavior and adverse patient outcomes. The recognized clinical impact of PNI highlights the need to better understand the molecular mechanisms underlying PNI-induced phenotypes. In this study, we isolated PNI-associated cancer-associated fibroblasts (pCAF), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared with non-PNI-associated CAFs. Single-cell, high-throughput sequencing and metabolomics data showed a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAF-derived lactate was absorbed by tumor cells, facilitating histone H3K18 lactylation. The lactate-induced epigenetic modification activated the transcription of neural invasion-associated genes, such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, which correlated with increased enzymatic activity and glycolytic flux. Targeting GAPDH and lactylation modifications significantly inhibited neural invasion in a genetically engineered mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Together, these findings provide critical insights into the role of CAFs in promoting PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC. SIGNIFICANCE: Targeting cancer-associated fibroblast metabolism or histone lactylation in pancreatic cancer cells to reverse epigenetic remodeling induced by lactate accumulation in the tumor microenvironment are potential therapeutic strategies to inhibit perineural invasion.
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