RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer
- Shuan Rao1,
- Verena Sigl1,
- Reiner Alois Wimmer1,
- Maria Novatchkova1,
- Alexander Jais2,3,
- Gabriel Wagner2,
- Stephan Handschuh4,
- Iris Uribesalgo1,
- Astrid Hagelkruys1,
- Ivona Kozieradzki1,
- Luigi Tortola1,
- Roberto Nitsch1,
- Shane J. Cronin1,
- Michael Orthofer1,
- Daniel Branstetter5,
- Jude Canon6,
- John Rossi7,
- Manolo D'Arcangelo8,
- Johan Botling9,
- Patrick Micke9,
- Linnea La Fleur9,
- Karolina Edlund10,
- Michael Bergqvist11,
- Simon Ekman12,
- Thomas Lendl13,
- Helmut Popper14,
- Hiroshi Takayanagi15,
- Lukas Kenner16,17,18,
- Fred R. Hirsch8,
- William Dougall6,19 and
- Josef M. Penninger1
- 1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna 1030, Austria;
- 2Department of Laboratory Medicine, Medical University Vienna, Vienna 1090, Austria;
- 3Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne 50931, Germany;
- 4VetCore Facility for Research, University of Veterinary Medicine, Vienna 1220, Austria;
- 5Department of Pathology, Amgen, Inc., Seattle, Washington 98119, USA;
- 6Department of Oncology Research, Amgen, Inc., Seattle, Washington 98119, USA;
- 7Department of Molecular Sciences, Amgen, Inc., Seattle, Washington 98119, USA;
- 8University of Colorado Cancer Center, Aurora, Colorado 80045, USA;
- 9Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala 75185, Sweden;
- 10Leibniz Research Center for Working Environment and Human Factors, Dortmund 44139, Germany;
- 11Department of Oncology, Gavle Hospital, Gavle 80187, Sweden;
- 12Department of Oncology–Pathology, Karolinska Institutet, Stockholm 17177, Sweden;
- 13Gregor Mendel Institute of Molecular Plant Biology (GMI), Vienna 1030, Austria;
- 14Research Unit Molecular Lung and Pleura Pathology, Institute of Pathology, Medical University Graz, Graz 8036, Austria;
- 15Department of Immunology, Tokyo University, Tokyo 108-8639, Japan;
- 16Department of Clinical Pathology, Medical University Vienna, Vienna 1090, Austria;
- 17Ludwig Boltzmann Institute for Cancer Research, Vienna 1090, Austria;
- 18Unit of Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, Vienna 1220, Austria
- Corresponding author: josef.penninger{at}imba.oeaw.ac.at
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.304162.117.
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Freely available online through the Genes & Development Open Access option.
- Received July 3, 2017.
- Accepted October 13, 2017.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.