Cancer‐Associated Fibroblast‐Derived Sphingosine‐1‐Phosphate Activates a MALL–SDC4 Axis to Facilitate Perineural Invasion in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) frequently exhibits perineural invasion (PNI), a clinicopathologic feature strongly associated with local recurrence and poor survival, yet lacking effective targeted interventions. By integrating patient cohorts with single-cell and bulk transcriptomics, multiplex immunofluorescence, and functional assays, this study defines a stromal-tumor signaling axis facilitating neural invasion. Cancer-associated fibroblasts (CAFs), particularly a myofibroblastic CAF-enriched population, upregulate sphingosine kinase 1 (SPHK1) and increase secretion of sphingosine-1-phosphate (S1P), which activates sphingosine-1-phosphate receptor 3 (S1PR3)/JNK/JUN signaling to transcriptionally induce MAL-like protein (MALL) in cancer cells. MALL binds to syndecan-4 (SDC4) and promotes its recycling to the plasma membrane, thereby increasing surface SDC4 abundance. This MALL-SDC4 program promotes RhoA/phosphorylated myosin light chain 2 (p-MLC2)-dependent amoeboid motility and sensitizes cancer cells to Schwann cell-derived pleiotrophin, strengthening directed neural invasion. Disruption of the axis through SPHK1 knockdown in CAFs, genetic perturbation of MALL or SDC4 in cancer cells, or adeno-associated virus-mediated SPHK1 or SDC4 knockdown in KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre) mice significantly reduces PNI and tumor burden. These findings uncover a metabolite-driven MALL-SDC4 program connecting stromal metabolism to neural invasion, and identify promising therapeutic targets for PDAC.