Abstract / Description
Pancreatic neuroendocrine tumors (pNETs) are biologically heterogeneous neoplasms with variable clinical outcomes. Current prognostic assessment relies largely on mitotic count and Ki-67 index, which may be affected by intratumoral heterogeneity and sampling bias. Additional biomarkers are therefore needed to refine risk stratification and characterize aggressive disease biology. Here, we investigated the prognostic and biological significance of Claudin-1 (CLDN1), a tight junction protein implicated in epithelial tumor progression. CLDN1 expression was assessed by immunohistochemistry in 67 surgically resected pNETs using tissue microarrays. A data-driven cutoff (H-score >50) identified a CLDN1-high subset associated with significantly shorter disease-specific survival (p = 0.009) and adverse clinicopathologic features. To define the molecular programs underlying CLDN1 overexpression, we analyzed RNA sequencing profiles from 22 tumors matched for key clinical variables by propensity score matching. CLDN1-high tumors showed attenuation of endocrine lineage markers and enrichment of exocrine and fetal ductal transcriptional programs. Cell-of-origin deconvolution further revealed a shift from endocrine alpha/beta-cell identity toward ductal or acinar-like states. Transcriptomic clustering demonstrated partial convergence between CLDN1-high pNETs and pancreatic ductal adenocarcinoma profiles. In addition, CLDN1-high tumors exhibited activation of epithelial-mesenchymal transition, HIPPO signaling, and immune-related pathways, together with increased stromal and immune cell infiltration. Collectively, our findings identify CLDN1 as a marker of a biologically distinct and clinically aggressive pNETs subset characterized by dedifferentiation, lineage plasticity, and tumor microenvironment remodeling, supporting further evaluation of CLDN1 as a candidate prognostic biomarker and potential therapeutic target in pNETs.