Work

A blood-based signature of cytoskeletal and extracellular remodeling for risk stratification of intraductal papillary mucinous neoplasms

Year: 2026

Type: preprint

Abstract: Background: Intraductal papillary mucinous neoplasms (IPMNs) are recognized as precursor lesions to pancreatic ductal adenocarcinoma (PDAC). However, the molecular programs underlying progression from low-grade dysplasia to advanced disease remain incompletely characterized. Herein, we performed an integrated plasma and tissue-proteomic analyses coupled with spatial and single-cell transcriptomics to identify biologically coherent remodeling programs reflected in circulation that distinguish IPMN by dysplasia grade and invasive disease. Methods: Using the O-link proximity extension assay platform, a panel of 1,104 proteins were quantified in plasma samples collected from patients with low-grade (LG) IPMN (n=30), high-grade (HG) IPMN with or without associated PDAC (IPMN/PDAC; n=40) and PDAC without IPMN (n=8). Predictive performance of individual biomarkers were assessed; likelihood ratio testing was performed to identify protein biomarkers that were complementarity with CA19-9 for risk of malignancy of IPMN. Findings were intersected with available spatial (N= 13) and single-cell (N= 6) transcriptomic datasets of IPMN tissues as well as mass spectrometry-based proteomic profiles of an independent set of resected human IPMN tissues (N= 9). Results: A total of 28, 43, and 35 circulating proteins were found to be differential in HG, IPMN/PDAC, and HG + IPMN/PDAC cases compared to LG IPMN. Among differential proteins were known PDAC-associated markers CEACAM5, CTRC, and REG3A as well as several biomarkers reflecting cytoskeletal and extracellular matrix remodeling and inflammatory processes. Focusing on cytoskeletal and ECM-related proteins and using likelihood ratio testing, an "OR" rule considering CA19-9, BGN, and ITGB1BP1 achieved overall sensitivity of 48.7% for HG + IPMN/PDAC, including 38.1% sensitivity for HG IPMN, at an overall specificity of 90%, which was improved compared to that of CA19-9 alone (overall sensitivity of 28.2%; McNemar Exact test 1-sided p-value: 0.011). Integrated proteomic and spatial transcriptomic datasets of IPMN tissues revealed coordinated alterations cytoskeletal and ECM remodeling and elevated matrix stiffness as prominent features associated with IPMN/PDAC, which paralleled concordant increases in BGN and ITGB1BP1. Cell-type of origin analyses based on spatial and single-cell data further revealed fibroblasts and myeloid cells as primary contributors to expression levels of BGN whereas ITGB1BP1 was primarily expressed in neoplastic epithelium. Conclusion: Advanced IPMN dysplasia and invasive disease are characterized by coordinated tissue remodeling programs that are systemically reflected in circulating proteomic profiles. Blood-based biomarkers identified through our study, such as BGN and ITB1BP1, have potential to improve upon CA19-9 for risk stratification of IPMN to better guide clinical management.

Source: medRxiv

DOI: 10.64898/2026.08.09.26360008