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Type of publication: Journal Article
Type of document: Full Paper

Year: 2017

Authors: 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

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

Source: Genes Dev. 2017; 31(20):2099-2112

Authors Vetmeduni Vienna:

Handschuh Stephan
Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals

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.© 2017 Rao et al.; Published by Cold Spring Harbor Laboratory Press.

Keywords Pubmed: Alveolar Epithelial Cellsmetabolism
Cell Respiration
Cells, Cultured
Energy Metabolism
Gonadal Steroid Hormonesphysiology
Lung Neoplasmsdrug therapymetabolism
Neoplastic Stem Cellsmetabolism
Proto-Oncogene Proteins p21(ras)genetics
Receptor Activator of Nuclear Factor-kappa Bantagonists & inhibitorsgeneticsmetabolismphysiology
Respiratory Mucosametabolism

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