Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis

Background: Early diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood stream. Here we explore the use of sAXL as a biomarker for PDAC. Methods: AXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models. Findings: AXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours.
This work was supported by grants from the Spanish Ministry of Science and Innovation (MICINN)/ Instituto de Salud Carlos III (ISCIII)-European Regional Development Fund (ERDF) (PI20/00625) and the “Generalitat de Catalunya” (2017/SGR/225) to PN; grants from the MICINN (Project# RTI2018-095672-BI00) to AM and PGdF; grant from the MICINN/ ISCIII-FEDER (PI20/01696) to MG and grant from the MICINN/ ISCIII-FEDER (PI18/01034) to AC. We also acknowledge grants from the Instituto de Salud Carlos III (ISCIII)/ERDF(PT20/00023) and the "Xarxa de Bancs de tumours” sponsored by Pla Director d'Oncologia de Catalunya (XBTC). PN’s lab is part of Redes de investigacion (Enfermedades Metabolicas y Cancer RED2018-102799-T), a project run by MINECO. CIBEREHD is funded by Instituto de Salud Carlos III.