Tumor-Associated Schwann Cell Remodeling under Metabolic Stress via Lactate Sensing Orchestrates
Description
Diabetes mellitus (DM) is a known risk factor for pancreatic cancer, but the underlying mechanisms remain elusive. Using in vivo models of diabetes-driven pancreatic tumorigenesis and metabolomics analysis, we demonstrate that metabolic stress induced by DM promotes pancreatic cancer progression by remodeling tumor-associated Schwann cells (TASs), impairing CD8+ T cell function. We discover that Mettl16+ Cd276+ Nectin2+ Schwann cells play a crucial role in mediating the pro-carcinogenic effects of lactate. Remodeled METTL16+ Schwann cells secret immune evasion factors (CD276, NECTIN2), contributing to anti-PD1 resistance. Furthermore, rosuvastatin was identified in this study as a novel METTL16 inhibitor for pancreatic cancer under metabolic stress. In conclusion, our study underscores the critical role of lactate in the metabolic reprogramming of pancreatic cancer mediated by Schwann cell remodeling, revealing novel pathways for therapeutic intervention. Biotin pull-down assay The Magic Dynabeads MyOne Streptavidin T1 were pre-incubated with free biotin or biotinylated lactate at room temperature for 30 minutes to saturate the bead surface with biotin. Subsequently, the pre-treated beads were mixed with the cell lysate of interest and incubated overnight at 4°C with rotation. The beads were then washed four times with PBS buffer to remove non-specifically bound molecules. After washing, the proteins were separated from the beads, and the presence and expression levels of the target protein were detected using techniques such as Western blotting or proteomics.