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Our analysis revealed that, compared with PDAC in stroma, PDAC with VI demonstrated up-regulation of genes associated with epithelial differentiation, classical subtype, and benign exocrine function. Conversely, PDAC with VI demonstrated down-regulation of genes associated with mesenchymal differentiation, basal-like subtype, and disease aggression. Additionally, we uncovered characteristics of VI morphology that correlated with these molecular features. VI\u2013intraepithelial neoplasia\u2013like foci had preserved venous architecture and had a classical, epithelial molecular phenotype, whereas VI-destructive foci had destroyed venous architecture and had a more basal-like, mesenchymal phenotype. We contextualized our findings using public RNA-seq data and observed that metastatic PDAC had greater similarity to PDAC in stroma than to PDAC with VI, whereas circulating tumor cells showed no preferential association. We confirmed our findings by spatial proteomic analysis of VI in an independent cohort of 19 treatment-na\u00efve patients with PDAC. Overall, our work provides a reference atlas of spatial transcriptomics and proteomics of VI in PDAC and reveals unexpected increases in molecular features associated with better patient outcomes.<\/jats:p>","DOI":"10.1126\/scitranslmed.ady7524","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T17:58:12Z","timestamp":1758736692000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["Spatial profiling of human pancreatic ductal adenocarcinoma reveals molecular alterations associated with venous invasion"],"prefix":"10.1126","volume":"17","author":[{"given":"Alexander T. 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