Woo-Yong Park1,5, Justin M. Gray1,2,5, Ronald J. Holewinski3, Thorkell Andresson3, Jae Young So1, Carmelo Carmona-Rivera 4, M. Christine Hollander1, Howard H. Yang1, Maxwell Lee 1, Steven D. Cappell 1 & Li Yang 1
1Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
2Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
3Protein Mass Spectrometry Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
4Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
5These authors contributed equally: Woo-Yong Park, Justin M. Gray
Corresponding author : Correspondence to Li Yang.
Most tumor cells undergo apoptosis in circulation and at the metastatic organ sites due to host immune surveillance and a hostile microenvironment. It remains to be elucidated whether dying tumor cells have a direct effect on live tumor cells during the metastatic process and what the underlying mechanisms are. Here we report that apoptotic cancer cells enhance the metastatic outgrowth of surviving cells through Padi4-mediated nuclear expulsion. Tumor cell nuclear expulsion results in an extracellular DNA–protein complex that is enriched with receptor for advanced glycation endproducts (RAGE) ligands. The chromatin-bound RAGE ligand S100a4 activates RAGE receptors in neighboring surviving tumor cells, leading to Erk activation. In addition, we identified nuclear expulsion products in human patients with breast, bladder and lung cancer and a nuclear expulsion signature correlated with poor prognosis. Collectively, our study demonstrates how apoptotic cell death can enhance the metastatic outgrowth of neighboring live tumor cells.