JSON
Rao S, Sigl V, Wimmer RA, Novatchkova M, Jais A, Wagner G, Handschuh S, Uribesalgo I, Hagelkruys A, Kozieradzki I, Tortola L, Nitsch R, Cronin SJ, Orthofer M, Branstetter D, Canon J, Rossi J, D'Arcangelo M, Botling J, Micke P, Fleur L, Edlund K, Bergqvist M, Ekman S, Lendl T, Popper H, Takayanagi H, Kenner L, Hirsch FR, Dougall W, Penninger JM
Genes Dev. 31 (20) 2099-2112 [2017-10-15; online 2017-11-08]
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 in mouse lung epithelial cells markedly impairs the progression of G12D KRas -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 G12D KRas -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.G12D
Clinical Genomics Uppsala [Collaborative]
PubMed 29118048
DOI 10.1101/gad.304162.117
Crossref 10.1101/gad.304162.117
pii: gad.304162.117
pmc: PMC5733500