Pancreatic ductal adenocarcinoma (PDAC) is marked by molecular heterogeneity and poor prognosis. Among the stemness‐related transcription factors, Spalt‐like Transcription Factor 4 (SALL4) is correlated with unfavorable outcomes; however, its roles in PDAC remain unclear.SALL4highexpression defines a PDAC subpopulation characterized by a shortened patient survival. AlthoughSALL4expression was mostly evaluated in tumor cells, our findings identify this embryonic transcription factor as a new biomarker in PDAC‐derived stroma. Gene expression analysis reveals that theSALL4highPDAC subset is enriched in cancer stem cell properties and stromal enrichment pathways; notably, an interaction with cancer‐associated fibroblasts (CAF) activated by TGF‐β. A particular oncogenic network was unraveled where Netrin‐1 and TGF‐β1 collaborate to induceSALL4expression in CAF and drive their cancer‐stemness‐promoting functions. A 7‐gene stromal signature related toSALL4highPDAC samples was highlighted and validated by immunochemistry for prognosis and clinical application. ThisSALL4‐related stroma discriminated pancreatic preinvasive from invasive lesions and was enriched in short‐term survivors. Our results show thatSALL4transcriptional activity controls a molecular network defined by a specific stromal signature that characterizes PDAC invasiveness and worse clinical outcomes.