| First Author | Rao S | Year | 2017 |
| Journal | Genes Dev | Volume | 31 |
| Issue | 20 | Pages | 2099-2112 |
| PubMed ID | 29118048 | Mgi Jnum | J:260458 |
| Mgi Id | MGI:6149676 | Doi | 10.1101/gad.304162.117 |
| Citation | Rao S, et al. (2017) RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer. Genes Dev 31(20):2099-2112 |
| abstractText | Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D) -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D) -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer. |
