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Nedd9 restrains autophagy to limit growth of early stage non-small cell lung cancer
Cancer Res. 2021 May 18;81(13) :3717-3726
PMID: 34006524    PMCID: PMC8277748    URL: https://www.ncbi.nlm.nih.gov/pubmed/34006524
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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 KRAS and TP53, 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 Kras mutation and Trp53 loss (KP mice), deletion of Nedd9 (KPN mice) led to the emergence of larger tumors characterized by accelerated rates of tumor growth and elevated proliferation. Orthotopic injection of KP and KPN tumors into the lungs of Nedd9-wildtype and -null mice indicated the effect of Nedd9 loss was cell-autonomous. Tumors in KPN 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. KPN tumors contained high levels of active LKB1 and AMPK and increased autophagy compared to KP 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.
1538-7445 Deneka, Alexander Y Kopp, Meghan C Orcid: 0000-0002-9761-0707 Nikonova, Anna S Gaponova, Anna V Kiseleva, Anna A Hensley, Harvey H Flieder, Douglas B Serebriiskii, Ilya G Golemis, Erica A Orcid: 0000-0003-3618-3673 Journal Article United States Cancer Res. 2021 May 18:canres.3626.2020. doi: 10.1158/0008-5472.CAN-20-3626.