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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2017

AutorInnen: 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

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

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

Autor/innen der Vetmeduni Vienna:

Handschuh Stephan
Kenner Lukas

Beteiligte Vetmed-Organisationseinheiten
Institut für Pathologie, Abteilung für Labortierpathologie

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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