Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway.

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.

Evaluation of the Pig-Tailed Macaque (Macaca nemestrina) as a Model of Human Staphylococcus aureus Nasal Carriage.

Staphylococcus aureus nasal carriage is a common condition affecting both healthy and immunocompromised populations and provides a reservoir for dissemination of potentially infectious strains by casual contact. The factors regulating the onset and duration of nasal S. aureus colonization are mostly unknown, and a human-relevant animal model is needed. Here, we screened 17 pig-tailed macaques (Macaca nemestrina) for S. aureus carriage, and 14 of 17 animals tested positive in the nose at one or both screening sessions (8 weeks apart), while the other 3 animals were negative in the nose but positive in the pharynx at least once. As in humans, S. aureus colonization was densest in the nose, and treatment of the nostrils with mupirocin ointment effectively cleared the nostrils and 6 extranasal body sites. Experimental nasal S. aureus colonization was established with 104 CFU/nostril, and both autologous and nonautologous strains survived over 40 days without any apparent adverse effects. A human nasal S. aureus isolate (strain D579, sequence type 398) was carried in 4 of 6 animals for over 3 weeks. Nostrils that did eradicate experimentally applied S. aureus exhibited neutrophilic innate immunity marked by elevated nasal interleukin-1ß (IL-1ß), IL-8, and monocyte chemotactic protein 1 levels and a 10-fold decreased IL-1 receptor antagonist/IL-1ß ratio within 7 days postinoculation, analogous to the human condition. Taken together, pig-tailed macaques represent a physiological model of human S. aureus nasal carriage that may be utilized for testing natural colonization and decolonization mechanisms as well as novel classes of anti-S. aureus therapeutics.