CD73 promotes non–small cell lung cancer metastasis by regulating Axl signaling independent of GAS6

Significance

Cancer metastasis is the dominant cause of mortality in non–small cell lung cancer (NSCLC) patients. Therefore, identification of metastasis-promoting molecules is important for cancer management and research. We demonstrate that CD73 was highly expressed in NSCLC tissues and cell lines, and overexpression of CD73 can promote NSCLC cell metastasis via the Axl/Smad3 signaling pathway. Moreover, we found that secreted CD73 can directly bind with site R55 located in Axl extracellular domain to serve as a ligand for Axl to induce its activation. Our findings indicated a role of CD73 in mediating NSCLC metastasis, especially for lung squamous cell cancer patients with high CD73 expression, combined targeting of AXL may provide the greatest benefit to patients.

Abstract

As catabolic enzyme, CD73 dephosphorylates adenosine monophosphate (AMP) and can also regulate tumor cell proliferation and metastasis. To date, very few studies have explored the role of CD73 in mediating non–small cell lung cancer (NSCLC) metastasis, and the underlying transducing signal has not been elucidated. In the present study, we demonstrated that the CD73/Axl axis could regulate Smad3-induced epithelial-to-mesenchymal transition (EMT) to promote NSCLC metastasis. Mechanically, CD73 can be secreted via the Golgi apparatus transport pathway. Then secreted CD73 may activate AXl by directly bind with site R55 located in Axl extracellular domain independently of GAS6. In addition, we proved that CD73 can stabilize Axl expression via inhibiting CBLB expression. We also identified the distinct function of CD73 activity in adenocarcinoma and squamous cell carcinoma. Our findings indicated a role of CD73 in mediating NSCLC metastasis and propose it as a therapeutic target for NSCLC.