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

Genes Dev. 2017 Oct 15;31(20):2099-2112. doi: 10.1101/gad.304162.117. Epub 2017 Nov 8.


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.

Keywords: RANK; energy homeostasis; lung cancer; lung cancer stem-like cells.

MeSH terms

  • Alveolar Epithelial Cells / metabolism
  • Animals
  • Cell Respiration
  • Cells, Cultured
  • Energy Metabolism
  • Female
  • Gonadal Steroid Hormones / physiology
  • Homeostasis
  • Humans
  • Lung / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Male
  • Mice
  • Mitochondria / metabolism
  • Neoplastic Stem Cells / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Receptor Activator of Nuclear Factor-kappa B / antagonists & inhibitors
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Receptor Activator of Nuclear Factor-kappa B / metabolism
  • Receptor Activator of Nuclear Factor-kappa B / physiology*
  • Respiratory Mucosa / metabolism


  • Gonadal Steroid Hormones
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • Tnfrsf11a protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)