<i>Nedd9</i> Restrains Autophagy to Limit Growth of Early Stage Non-Small Cell Lung Cancer.

Abstract

Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. With overall 5-year survival estimated at <17%, it is critical to identify factors that regulate NSCLC disease prognosis. NSCLC is commonly driven by mutations in <i>KRAS</i> and <i>TP53</i>, with activation of additional kinases such as SRC promoting tumor invasion. In this study, we investigated the role of NEDD9, a SRC activator and scaffolding protein, in NSCLC tumorigenesis. In an inducible model of NSCLC dependent on <i>Kras</i> mutation and <i>Trp53</i> loss (<i>KP</i> mice), deletion of <i>Nedd9</i> (<i>KPN</i> mice) led to the emergence of larger tumors characterized by accelerated rates of tumor growth and elevated proliferation. Orthotopic injection of <i>KP</i> and <i>KPN</i> tumors into the lungs of <i>Nedd9</i>-wild-type and -null mice indicated the effect of <i>Nedd9</i> loss was cell-autonomous. Tumors in <i>KPN</i> mice displayed reduced activation of SRC and AKT, indicating that activation of these pathways did not mediate enhanced growth of KPN tumors. NSCLC tumor growth has been shown to require active autophagy, a process dependent on activation of the kinases LKB1 and AMPK. <i>KPN</i> tumors contained high levels of active LKB1 and AMPK and increased autophagy compared with <i>KP</i> tumors. Treatment with the autophagy inhibitor chloroquine completely eliminated the growth advantage of KPN tumors. These data for the first time identify NEDD9 as a negative regulator of LKB1/AMPK-dependent autophagy during early NSCLC tumor growth. SIGNIFICANCE: This study demonstrates a novel role for the scaffolding protein NEDD9 in regulating LKB1-AMPK signaling in early stage non-small cell lung cancer, suppressing autophagy and tumor growth.