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. SALL4 expression defines a PDAC subpopulation characterized by a shortened patient survival. Although SALL4 expression 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 the SALL4 PDAC 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 induce SALL4 expression in CAF and drive their cancer-stemness-promoting functions. A 7-gene stromal signature related to SALL4 PDAC samples was highlighted and validated by immunochemistry for prognosis and clinical application. This SALL4-related stroma discriminated pancreatic preinvasive from invasive lesions and was enriched in short-term survivors. Our results show that SALL4 transcriptional activity controls a molecular network defined by a specific stromal signature that characterizes PDAC invasiveness and worse clinical outcomes.
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