Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: a bottom‐up approach

• DOI: 10.1002/path.6398
• Publication Date: 2025-02-12T06:29:22Z
• Authors: Marc Hilmi; Flore Delecourt; Jérôme Raffenne; Taib Bourega; Nelson Dusetti; Juan Iovanna; Yuna Blum; Magali Richard; Cindy Neuzillet; Anne Couvelard; Matthieu Tihy; Louis de Mestier; Vinciane Rebours; Rémy Nicolle; Jérôme Cros
• Keywords: Tissue microarray; Basal (medicine)

Abstract Pancreatic ductal adenocarcinoma (PDAC) tumor interpatient heterogeneity has been well described with two major prognostic subtypes (classical and basal‐like). An important intrapatient reported but not yet studied extensively due to the lack of standardized, reproducible, easily accessible high‐throughput methods. We built an immunohistochemical (IHC) tool capable differentiating RNA‐defined classical basal‐like tumors by selecting relevant antibodies using a multistep process. The successive stages (i) in silico selection from literature review bulk transcriptome analysis 309 PDACs, (ii) tumor‐specific 30 patient‐derived xenografts single‐cell data, followed (iii) validation on tissue microarrays 50 PDAC were conducted. used our final IHC panel independent cohorts resected ( n = 95, whole‐slide, 148, microarrays) for external validation. After digitization registration pathology slides, we performed tile‐based areas identify marker combinations. Sequential led following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes identified: one classical, intermediate (KRT17+), (MUC16+ versus S100A2+) specific biological properties. presence minor basal contingent drastically reduced overall survival [hazard ratio (HR) 1.90, p 0.03], even predominant PDACs. Analysis preneoplastic lesions suggested that pancreatic carcinogenesis might follow progressive evolution toward through early phenotype. In conclusion, redefined assessed high degree intra‐ intertumoral PDAC. © 2025 Author(s). Journal Pathology published John Wiley & Sons Ltd behalf Pathological Society Great Britain Ireland.