Abstract 3049: Hornerin as a novel therapeutic target for pancreatic cancer
Authors: Julien Dimastromatteo, Kimberly A. Kelly
Journal: Cancer Research (2019)

Abstract Background and aim - Through our functional proteomics screening efforts, we recently identified hornerin (HRNR) as a protein expressed on the cell surface of both cancer and cancer blood vessels. Hornerin is a member of the S100 family of proteins, a group of calcium binding proteins involved in the maintenance of calcium homeostasis, as well other fundamental cellular processes and signaling cascades. Several family members have been implicated in a variety of cancers, with evidence demonstrating that altered expression of S100 proteins was associated with tumor progression and prognosis. Therefore, we hypothesized that HRNR may represent an important therapeutic target for cancer. Method - De-identified human tumor microarray specimens underwent standard immunohistochemistry (IHC) procedure to determine HRNR expression in various type of cancer. Standard westernblot were also used to assess HRNR expression in eleven epithelial PDAC cell lines. Analysis of HRNR expression in cellular compartments was performed after differential centrifugation of PDAC cell lysates. Cell surface HRNR expression was further validated by immunofluorescence on non-permeabilized cells. Additionally, cells from 4 different renal carcinoma (RCC) PDX models were infected with human HRNR shRNA lentiviral particles in order to silence HRNR expression. Those cells were then injected subcutaneously into immunocompromised nude mice and assessed for tumor growth. Molecular mechanism of HRNR was evaluated via western blot. Effect of blocking HRNR on cancer in vitro and in vivo using a HRNR specific antibody was determined. Results - Based on IHC scoring, HRNR expression has been observed in twenty-one different types of cancer among which are PDAC and renal cancer. Expression of HRNR in tumor cells and on the cell surface of cancer was confirmed through cell fractionation and immunofluorescence. Validation of HRNR as an important cancer therapeutic target was demonstrated through siRNA knockout studies. PDX models of renal cancer that were devoid of HRNR expression were unable to form tumors in vivo. As members of the S100 family have been shown to activate signaling pathways important for proliferation and migration, we hypothesized that HRNR would be able to activate proteins in these signaling cascades. Western blot analysis of cells treated with recombinant HRNR revealed the activation of AKT and ERK and the stabilization of EGFR. Therefore, we evaluated the efficacy of a HRNR targeted antibody as a therapeutic. Treatment with the HRNR targeted antibody resulted in a decrease in cell proliferation and complete cell death that was HRNR specific. Conclusion - HRNR plays an important role in cancer and represents a novel therapeutic target. Citation Format: Julien Dimastromatteo, Kimberly A. Kelly. Hornerin as a novel therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3049.