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

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.

Screening for Interacting Proteins with Peptide Biomarker of Blood–Brain Barrier Alteration under Inflammatory Conditions

“…An in vitro study using phage display screening on the endothelial protein vascular adhesion protein-1 (VAP-1) identified a specific ligand peptide, denominated Siglec-9, with potential imaging biomarker properties [ 56 ]. Another study tested an in vivo phage display screening strategy to identify a specific peptide ligand to pancreatic tumor vasculature [ 57 ]. The authors used a functional proteomics approach to identify the potential target protein, similar to the approach that we used here.…”

Challenges in the development of nanoparticle‐based imaging agents: Characterization and biology

“…In an in vivo phage display screen, animals are euthanized and perfused after the desired time point (~5–10 min for identifying phage specific for endothelium, or ~4–6 hr for identifying phage specific for cells within a desired tissue) following i.v. administration and phage is recovered from the tissue or a section of tissue by homogenizing and amplifying in Escherichia coli (Siva Sai Krishna Dasa et al, 2015; Deramchia et al, 2012; Gutknecht et al, 2017; Hemadou et al, 2018). Target specific phage is amplified in bacteria, and by doing additional rounds of selection, high affinity phage clones can be obtained.…”

Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin‐hornerin (FlgHrnr−/−) double‐deficient mice

“…Similar to FLG, HRNR protein is per se expressed in healthy epidermis, increased in skin barrier impaired epidermis, and reduced in the skin of patients with atopic dermatitis (AD) and hand eczema . Besides the function as structural cornified envelope protein, HRNR was reported to have a role for tumor development . However, up to now, it is not clear whether Hrnr is a tumor suppressor or tumor promotor …”