Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis
Neus Martínez-Bosch,
Helena Cristóbal,
Mar Iglesias,
Meritxell Gironella,
Luis Barranco,
Laura Visa,
Domenico Calafato,
Silvia Jiménez-Parrado,
Julie Earl,
Alfredo Carrato,
Noemí Manero-Rupérez,
Mireia Moreno,
Albert Morales,
Carmen Guerra,
Pilar Navarro,
Pablo García de Frutos
Affiliations
Neus Martínez-Bosch
Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
Helena Cristóbal
Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB)-CSIC and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
Mar Iglesias
Department of Pathology, Autonomous University of Barcelona, Hospital del Mar, Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Barcelona, Spain
Meritxell Gironella
Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD); Hospital Clínic of Barcelona and IDIBAPS; Barcelona, Spain
Luis Barranco
Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain; Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
Laura Visa
Department of Medical Oncology, Hospital del Mar, Barcelona, Spain
Domenico Calafato
Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB)-CSIC and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
Silvia Jiménez-Parrado
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
Julie Earl
Molecular Epidemiology and Predictive Tumour Markers Group, Medical Oncology Research Laboratory, Ramón y Cajal Health Research Institute (IRYCIS), Madrid, Spain. CIBERONC
Alfredo Carrato
Molecular Epidemiology and Predictive Tumour Markers Group, Medical Oncology Research Laboratory, Ramón y Cajal Health Research Institute (IRYCIS), Madrid, Spain. CIBERONC
Noemí Manero-Rupérez
Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
Mireia Moreno
Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
Albert Morales
Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, CIBEREHD and IDIBAPS, Barcelona, Spain
Carmen Guerra
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
Pilar Navarro
Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB)-CSIC and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Corresponding authors.
Pablo García de Frutos
Department of Cell Death and Proliferation, IIBB-CSIC, Unidad Asociada IMIM/IIBB-CSIC; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), and IDIBAPS, Barcelona, Spain; Corresponding authors.
Summary: 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. Interpretation: sAXL appears as a biomarker for early detection of PDAC and PDAC–CP discrimination that could accelerate treatment and improve its dismal prognosis. Funding: This work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya.
