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By integrating patient cohorts with single\u2010cell and bulk transcriptomics, multiplex immunofluorescence, and functional assays, this study defines a stromal\u2010tumor signaling axis facilitating neural invasion. Cancer\u2010associated fibroblasts (CAFs), particularly a myofibroblastic CAF\u2010enriched population, upregulate sphingosine kinase 1 (SPHK1) and increase secretion of sphingosine\u20101\u2010phosphate (S1P), which activates sphingosine\u20101\u2010phosphate receptor 3 (S1PR3)\/JNK\/JUN signaling to transcriptionally induce MAL\u2010like protein (MALL) in cancer cells. MALL binds to syndecan\u20104 (SDC4) and promotes its recycling to the plasma membrane, thereby increasing surface SDC4 abundance. This MALL\u2013SDC4 program promotes RhoA\/phosphorylated myosin light chain 2 (p\u2010MLC2)\u2010dependent amoeboid motility and sensitizes cancer cells to Schwann cell\u2010derived 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\u2010associated virus\u2010mediated SPHK1 or SDC4 knockdown in KPC (\n                    <jats:italic>Kras<\/jats:italic>\n                    <jats:sup>LSL\u2010G12D\/+<\/jats:sup>\n                    ;\n                    <jats:italic>Trp53<\/jats:italic>\n                    <jats:sup>LSL\u2010R172H\/+<\/jats:sup>\n                    ;\n                    <jats:italic>Pdx1<\/jats:italic>\n                    \u2010Cre) mice significantly reduces PNI and tumor burden. These findings uncover a metabolite\u2010driven MALL\u2013SDC4 program connecting stromal metabolism to neural invasion, and identify promising therapeutic targets for PDAC.\n                  <\/jats:p>","DOI":"10.1002\/advs.75426","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:43:51Z","timestamp":1776854631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cancer\u2010Associated Fibroblast\u2010Derived Sphingosine\u20101\u2010Phosphate Activates a MALL\u2013SDC4 Axis to Facilitate Perineural Invasion in Pancreatic Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Wang","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 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