The autotaxin - lysophosphatidic acid axis promotes lung carcinogenesis

Pathogenesis and progression of lung cancer (LC) are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid which is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six, G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of LC 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 LC. ENPP2 was genetically altered in 8% of LC patients, while increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in LC patients. Comparable observations were made in the two most widely used animal models of LC, the carcinogen urethane (URE) -induced and the genetically engineered K-rasG12D-driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a pro-carcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the pro-carcinogenic effects of the ATX/LPA axis in K-ras-G12D-driven LC pathogenesis.

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