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

Author:

Rao Shuan,Sigl Verena,Wimmer Reiner Alois,Novatchkova Maria,Jais Alexander,Wagner Gabriel,Handschuh Stephan,Uribesalgo Iris,Hagelkruys Astrid,Kozieradzki Ivona,Tortola Luigi,Nitsch Roberto,Cronin Shane J.,Orthofer Michael,Branstetter Daniel,Canon Jude,Rossi John,D'Arcangelo Manolo,Botling Johan,Micke Patrick,Fleur Linnea La,Edlund Karolina,Bergqvist Michael,Ekman Simon,Lendl Thomas,Popper Helmut,Takayanagi Hiroshi,Kenner Lukas,Hirsch Fred R.,Dougall William,Penninger Josef M.ORCID

Abstract

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.

Funder

National Cancer Institute

Colorado Lung Cancer

Specialized Program for Research Excellence (SPORE) Program

Austrian Science Fund

Marie-Sklodowska-Curie-Initial Training Networks

ALKATRAS Network

Institute of Molecular Biotechnology

Austrian Academy of Sciences

Austrian Ministry of Sciences

European Research Council

Era of Hope Innovator award

Publisher

Cold Spring Harbor Laboratory

Subject

Developmental Biology,Genetics

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