Tissue-based multiomic exploratory analysis of the urokinase plasminogen activator/uPAR system and matrix metalloproteinases in Stroma AReactive Invasion Front Areas-positive gastrointestinal cancers
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...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
August 2026
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| In: |
Pathobiology
Year: 2026, Volume: 93, Issue: 4, Pages: 200-211 |
| ISSN: | 1423-0291 |
| DOI: | 10.1159/000549919 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1159/000549919
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| Author Notes: | Nic G. Reitsam, Bianca Grosser, Sebastian Dintner, Veselin Grozdanov, Florian Sommer, Christian Heyer, Matthias Schlesner, Jochen Hardt, Simon Franz, Gerhard Schenkirsch, Andreas Probst, Phillip Löhr, Johanna Waidhauser, Bruno Märkl |
| Summary: | 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. Cancer cells constantly interact with their surrounding tissue, and some of these interactions may help tumours to grow faster and be more aggressive. At the edge of some cancers, tumour cells grow directly into adipose tissue without intervening stromal reaction. We as pathologists call these areas SARIFA (Stroma AReactive Invasion Front Areas). SARIFA positivity has been shown to be an adverse risk factor in gastrointestinal cancers. However, it is unclear why and how it arises. We studied now whether genes and proteins that help tumours break down their surrounding tissue are linked to SARIFA. Tumours with SARIFA positivity more often showed higher levels of the plasmin/plasminogen activator system and its associated downstream metalloproteinases. Spatial data indicated more PLAU expression in tumour cells and more PLAUR expression in nearby stromal cells, suggesting a close interaction between them. Moreover, SARIFA-positive tumours had more small clusters of invasive cells, so-called tumour buds, which are also characteristic for an aggressive behaviour. Overall, our results help better understand the biology behind SARIFA and highlight a pathway that might be targetable. |
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| Item Description: | Veröffentlicht online: January 16, 2026 Gesehen am 27.07.2026 |
| Physical Description: | Online Resource |
| ISSN: | 1423-0291 |
| DOI: | 10.1159/000549919 |