Identification of the S100 fused-type protein hornerin as a regulator of tumor vascularity

Michael F. Gutknecht, Marc E. Seaman, Bo Ning, Daniel Auger Cornejo, Emily Mugler, Patrick F. Antkowiak, Christopher A. Moskaluk, Song Hu, Frederick H. Epstein and Kimberly A. Kelly ()
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Michael F. Gutknecht: The University of Virginia
Marc E. Seaman: The University of Virginia
Bo Ning: The University of Virginia
Daniel Auger Cornejo: The University of Virginia
Emily Mugler: The University of Virginia
Patrick F. Antkowiak: The University of Virginia
Christopher A. Moskaluk: The University of Virginia
Song Hu: The University of Virginia
Frederick H. Epstein: The University of Virginia
Kimberly A. Kelly: The University of Virginia

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Sustained angiogenesis is essential for the development of solid tumors and metastatic disease. Disruption of signaling pathways that govern tumor vascularity provide a potential avenue to thwart cancer progression. Through phage display-based functional proteomics, immunohistochemical analysis of human pancreatic ductal carcinoma (PDAC) specimens, and in vitro validation, we reveal that hornerin, an S100 fused-type protein, is highly expressed on pancreatic tumor endothelium in a vascular endothelial growth factor (VEGF)-independent manner. Murine-specific hornerin knockdown in PDAC xenografts results in tumor vessels with decreased radii and tortuosity. Hornerin knockdown tumors have significantly reduced leakiness, increased oxygenation, and greater apoptosis. Additionally, these tumors show a significant reduction in growth, a response that is further heightened when therapeutic inhibition of VEGF receptor 2 (VEGFR2) is utilized in combination with hornerin knockdown. These results indicate that hornerin is highly expressed in pancreatic tumor endothelium and alters tumor vessel parameters through a VEGF-independent mechanism.

Date: 2017
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DOI: 10.1038/s41467-017-00488-6

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