期刊
GENES & DEVELOPMENT
卷 31, 期 20, 页码 2099-2112出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.304162.117
关键词
RANK; energy homeostasis; lung cancer; lung cancer stem-like cells
资金
- National Cancer Institute/Colorado Lung Cancer Specialized Program for Research Excellence (SPORE) Program
- Austrian Science Fund (FWF) [P26011]
- Marie-Sklodowska-Curie-Initial Training Networks (MCEU-ITN) ALKATRAS Network [675712]
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences
- Austrian Ministry of Sciences
- Austrian Academy of Sciences
- European Research Council Advanced Grant
- Era of Hope Innovator award
- Marie Curie Actions (MSCA) [675712] Funding Source: Marie Curie Actions (MSCA)
- Grants-in-Aid for Scientific Research [15H05703] Funding Source: KAKEN
- Austrian Science Fund (FWF) [P26011] Funding Source: Austrian Science Fund (FWF)
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.
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