EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma

Shinya Sato; Masatoshi Nakagawa; Takeshi Terashima; Soichiro Morinaga; Yohei Miyagi; Eisaku Yoshida; Toru Yoshimura; Motoharu Seiki; Shuichi Kaneko; Makoto Ueno; Taro Yamashita; Naohiko Koshikawa

doi:10.1158/2767-9764.CRC-23-0087

EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma

Cancer Res Commun. 2023 Sep 15;3(9):1862-1874. doi: 10.1158/2767-9764.CRC-23-0087.

Authors

Shinya Sato^#^{1

2

3}, Masatoshi Nakagawa^#^{4

5}, Takeshi Terashima⁶, Soichiro Morinaga⁷, Yohei Miyagi^{1

2}, Eisaku Yoshida³, Toru Yoshimura³, Motoharu Seiki⁸, Shuichi Kaneko⁸, Makoto Ueno⁹, Taro Yamashita⁸, Naohiko Koshikawa^{5

10}

Affiliations

¹ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
² Department of Pathology, Kanagawa Cancer Center Hospital, Yokohama, Japan.
³ Morphological Analysis Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
⁴ Research and Development, Abbott Japan LLC, Chiba, Japan.
⁵ Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.
⁶ Advanced Preventive Medical Sciences Research Center, Kanazawa University Hospital, Kanazawa, Japan.
⁷ Department of Gastroenterological Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan.
⁸ Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
⁹ Department of Gastroenterology, Kanagawa Cancer Center Hospital, Yokohama, Japan.
¹⁰ Clinical Cancer Proteomics Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, Japan.

^# Contributed equally.

Abstract

Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in sera from patients with pancreatic ductal carcinoma. We established a quantitative automated chemiluminescence immunoassay for EphA2-NF and evaluated serum EphA2-NF levels as a biomarker to diagnose pancreatic ductal carcinoma in the test and validation cohorts. The EphA2-NF value was elevated (above the cutoff: mean ± SD) in more than half of the patients with stage I/II pancreatic ductal carcinoma. Among patients receiving standard chemotherapy for pancreatic ductal carcinoma [gemcitabine plus nab-paclitaxel (GnP)], the median survival time of patients with elevated serum EphA2-NF was half that of patients with values below the cutoff. Patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous pancreatic ductal carcinoma lesion, also show high serum EphA2 levels, which are associated with an increase in pancreatic duct size and the development of pancreatic ductal carcinoma in some cases. IHC showed loss of EphA2-NF staining in IPMN with pancreatic ductal carcinoma, but not in the normal epithelium or IPMN without pancreatic ductal carcinoma, regardless of the histologic grade. These results suggest that EphA2 cleavage is an essential event that occurs very early in pancreatic ductal carcinoma development, and that the consequent release of EphA2-NF can be detected in the serum. Thus, serum EphA2-NF could be a diagnostic biomarker for very early-stage pancreatic ductal carcinoma and pancreatic ductal carcinoma development from high-risk IPMN and as a prognostic biomarker after chemotherapy with GnP.

Significance: EphA2 N-terminus deletion is involved in pancreatic ductal carcinoma development from high-risk IPMN and EphA2-NF produced by cleavage can be used as a serum biomarker to diagnose pancreatic ductal carcinoma and predict pancreatic ductal carcinoma development from high-risk IPMN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / diagnosis
Humans
Pancreatic Intraductal Neoplasms*
Pancreatic Neoplasms* / diagnosis
Peptide Hydrolases
Proteolysis

Substances

Peptide Hydrolases