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

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

Author information

1
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna 1030, Austria.
2
Department of Laboratory Medicine, Medical University Vienna, Vienna 1090, Austria.
3
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne 50931, Germany.
4
VetCore Facility for Research, University of Veterinary Medicine, Vienna 1220, Austria.
5
Department of Pathology, Amgen, Inc., Seattle, Washington 98119, USA.
6
Department of Oncology Research, Amgen, Inc., Seattle, Washington 98119, USA.
7
Department of Molecular Sciences, Amgen, Inc., Seattle, Washington 98119, USA.
8
University of Colorado Cancer Center, Aurora, Colorado 80045, USA.
9
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala 75185, Sweden.
10
Leibniz Research Center for Working Environment and Human Factors, Dortmund 44139, Germany.
11
Department of Oncology, Gavle Hospital, Gavle 80187, Sweden.
12
Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17177, Sweden.
13
Gregor Mendel Institute of Molecular Plant Biology (GMI), Vienna 1030, Austria.
14
Research Unit Molecular Lung and Pleura Pathology, Institute of Pathology, Medical University Graz, Graz 8036, Austria.
15
Department of Immunology, Tokyo University, Tokyo 108-8639, Japan.
16
Department of Clinical Pathology, Medical University Vienna, Vienna 1090, Austria.
17
Ludwig Boltzmann Institute for Cancer Research, Vienna 1090, Austria.
18
Unit of Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, Vienna 1220, Austria.

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.

KEYWORDS:

RANK; energy homeostasis; lung cancer; lung cancer stem-like cells

PMID:
29118048
PMCID:
PMC5733500
DOI:
10.1101/gad.304162.117
[Indexed for MEDLINE]
Free PMC Article

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