Tumor Biology and Immunology The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis Christiana Magkrioti 1 , Nikos Oikonomou 1 , Eleanna Kaffe 1 , Marios-Angelos Mouratis 1 , Nikos Xylourgidis 1 , Iliana Barbayianni 1 , Petros Megadoukas 1 , Vaggelis Harokopos 1 , Christos Valavanis 2 , Jerold Chun 3 , Alexandra Kosma 4 , Georgios T. Stathopoulos 5,6 , Evangelos Bouros 7 , Demosthenes Bouros 7 , Konstantinos Syrigos 8 , and Vassilis Aidinis 1 Abstract Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epige- netic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor–like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotro- pic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit over- lapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Com- parable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane–induced and the genetically engineered K-ras G12D –driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras- G12D –driven lung cancer pathogenesis. Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634–44. Ó2018 AACR. Introduction Lung cancer is the most prevalent form of malignancy and the leading cause of global cancer-related mortality; the prognosis for patients with lung cancer remains dismal, with a 5-year survival rate below 20%, for all disease stages combined. The major (85%) histological subtype of lung cancer is non–small cell lung cancer (NSCLC), which is further subdivided to adeno- carcinoma (ADC; 40%), squamous cell carcinoma (SCC; 25%–30%), and large cell carcinoma (LCC; 10%–15%; ref. 1). The molecular origins of lung cancer lie in complex interac- tions between the environment and host genetic susceptibility, further modulated by genetic and epigenetic changes, leading to changes in the activation status of oncogenes and tumor suppressor genes (1). However, lung cancer, and especially NSCLC, is considered as a group of distinct diseases with vast genetic and cellular heterogeneity and although some genomic alterations are shared among various histologic types, most alterations remain distinct (2). The identified genomic altera- tions are not always associated with the activation of the relevant cellular pathways and the corresponding phenotypic aberrations (3), thus further increasing the complexity of cor- relating genotypic and phenotypic data. Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), more commonly known as autotaxin (ATX), is a secreted glycoprotein widely present in biological fluids. ATX catalyzes the extracellular hydrolysis of circulating and/or de novo pro- duced lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA; ref. 4). LPA, whose levels are catabolized by phospho- lipid phosphatases (PLPP; ref. 5), is a pleiotropic phospholipid mediator that evokes growth factor–like responses such as cell growth, survival, differentiation and motility, in most cell types (6). The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPAR), exhibiting overlapping specificities and widespread distribution (7). The orphan GPR87 and P2Y10 receptors, as well as the receptor for advanced glycation end products (RAGE) and the intracellular peroxisome proliferator-activated receptor g (PPARg ), have also been suggested to mediate LPA signaling (4, 7). 1 Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming," Greece. 2 Department of Pathology, Metaxa Cancer Hospital, Greece. 3 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. 4 First Pulmonary Clinic, Papanikolaou General Hospital, Greece. 5 Department of Physiology, Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras, Patras, Greece. 6 Comprehensive Pneumology Center and Institute for Lung Biology and Disease, University Hospital, Ludwig- Maximilian University and Helmholtz Zentrum M€ unchen, Germany. 7 Academic Department of Pneumonology, University of Athens, Athens, Greece. 8 Oncology Unit, Sotiria Hospital, School of Medicine, University of Athens, Athens, Greece. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Corresponding Author: Vassilis Aidinis, Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming," Fleming 34, 16672 Athens, Greece. Phone: 302109654382; Fax: 302109654210; E-mail: V.Aidinis@Fleming.gr doi: 10.1158/0008-5472.CAN-17-3797 Ó2018 American Association for Cancer Research. Cancer Research Cancer Res; 78(13) July 1, 2018 3634 on May 24, 2020. © 2018 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst May 3, 2018; DOI: 10.1158/0008-5472.CAN-17-3797