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

作者：Marc Hilmi, F. 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 · 发表于：The Journal of Pathology · 年份：2025 · DOI：10.1002/path.6398 · 被引用次数：11 · 研究领域：Pancreatic and Hepatic Oncology Research、Cancer Genomics and Diagnostics、Renal and related cancers

Pancreatic ductal adenocarcinoma (PDAC) tumor interpatient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intrapatient heterogeneity has been reported but has not yet been studied extensively due to the lack of standardized, reproducible, and easily accessible high-throughput methods. We built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multistep process. The successive stages of (i) an in silico selection from a literature review and a bulk transcriptome analysis of 309 PDACs, (ii) a tumor-specific selection from 30 patient-derived xenografts and single-cell data, followed by (iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n = 95, whole-slide, n = 148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based analysis in tumor areas to identify relevant marker combinations. Sequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: one classical, one intermediate (KRT17+), and two basal-like (MUC16+ versus S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival [hazard ratio (HR) = 1.90, p...