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RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer.

Shuan RaoVerena SiglReiner Alois WimmerMaria NovatchkovaAlexander JaisGabriel WagnerStephan HandschuhIris UribesalgoAstrid HagelkruysIvona KozieradzkiLuigi TortolaRoberto NitschShane J CroninMichael OrthoferDaniel BranstetterJude CanonJohn RossiManolo D'ArcangeloJohan BotlingPatrick MickeLinnea La FleurKarolina EdlundMichael BergqvistSimon EkmanThomas LendlHelmut PopperHiroshi TakayanagiLukas KennerFred R HirschWilliam DougallJosef M Penninger
Published in: Genes & development (2017)
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 KRasG12D in mouse lung epithelial cells markedly impairs the progression of KRasG12D -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 KRasG12D -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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