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Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
Tissue-Based Multiomic Exploratory Analysis of the Urokinase Plasminogen Activator/uPAR System and Matrix
Nic G Reitsam1,2, Bianca Grosser3,4,5, Sebastian Dintner6,7
1Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany, nic.reitsam@uka-science.de.
Abstract:
Introduction: We recently proposed SARIFA (Stroma AReactive Invasion Front Areas), defined as direct tumour-adipocyte interaction, as an H&E-based histopathologic biomarker in gastrointestinal cancers, particularly gastric cancer (GC) and colorectal cancer (CRC). Despite SARIFA's well-validated prognostic value, its mechanistic underpinnings remain unclear. We hypothesized that extracellular matrix remodelling, specifically the plasmin/plasminogen activator system, may contribute to SARIFA formation.
Methods:
To test this, we compared the prognostic value of H&E-based SARIFA status with enzyme-linked immunosorbent assay (ELISA)-based protein levels of the serine proteases urokinase-type plasminogen activator (uPA, encoded by PLAU) and plasminogen activator inhibitor-1 (PAI-1, encoded by SERPINE1) in CRC. We further examined associations between SARIFA status and the plasmin/plasminogen activator system as well as downstream metalloproteinases using both protein (ELISA, immunohistochemistry) and bulk gene expression data (TCGA-COAD/READ and TCGA-STAD), as well as spatial gene expression profiling in CRC (n = 8) and GC (n = 12).
Results:
Our findings show that high expression of the plasmin/plasminogen activator system and downstream metalloproteinases correlates with SARIFA positivity. Digital spatial profiling revealed PLAU upregulation in tumour cells and PLAUR (encoding uPAR) upregulation in adjacent stromal cells at SARIFAs, suggesting a potential receptor-ligand interaction. Notably, SARIFA-positive tumours showed significantly higher numbers of tumour buds.
Conclusion:
These results provide new insights into the biological basis of SARIFAs and suggest therapeutic vulnerabilities related to the plasmin/plasminogen activator system.
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