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RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer
Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
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2017 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, no 20, p. 2099-2112Article in journal (Refereed) Published
Abstract [en]

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 KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-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 KRas(G12D)-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.

Place, publisher, year, edition, pages
2017. Vol. 31, no 20, p. 2099-2112
Keywords [en]
RANK, energy homeostasis, lung cancer, lung cancer stem-like cells
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-342920DOI: 10.1101/gad.304162.117ISI: 000415923700007PubMedID: 29118048OAI: oai:DiVA.org:uu-342920DiVA, id: diva2:1185705
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26Bibliographically approved

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