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.
Highlights
The receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) is an essential cytokine that, upon binding to its cognate receptor, receptor activator of nuclear factor-kB (RANK), selectively activates intercellular signaling pathways to act as an essential regulator of osteoclastogenesis (Kong et al 1999; Leibbrandt and Penninger 2008)
We analyzed 120 human lung tissue samples of non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) and detected strong tumoral RANK expression in each lung cancer histotype; the incidence and intensity of expression were greatest in adenocarcinomas, with 72% of lung adenocarcinomas staining positive for RANK (Fig. 1A; Supplemental Fig. S1A)
In the Uppsala lung cancer cohort, RANK positivity was significantly associated with the presence of KRas mutations (Fig. 1B)
Summary
The receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) is an essential cytokine that, upon binding to its cognate receptor, RANK, selectively activates intercellular signaling pathways to act as an essential regulator of osteoclastogenesis (Kong et al 1999; Leibbrandt and Penninger 2008). We and others have shown recently that RANKL/RANK are involved in hormone- and Brca1-driven breast cancer in mice (Schramek et al 2010; Nolan et al 2016; Sigl et al 2016). RANKL inhibition with a monoclonal antibody called denosumab has been approved for osteoporosis and skeletal-related events in cancer (Branstetter et al 2012; Brown-Glaberman and Stopeck 2013) and has been linked to delayed reoccurrence of breast tumors in an adjuvant setting (Gnant et al 2015). Since the RANKL/RANK system is known to be regulated by sex hormones (Fata et al 2000; Beleut et al 2010), we hypothesized that it might have a direct role in primary lung cancer
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