Protein citrullination catalyzed by Peptidylarginine deiminase (PADI) is a critical regulatory mechanism in physiology and pathology conditions. In cancer, PADI4 is highly expressed in metastatic tumor cells and citrullinates histone H3, leading to loss of the positive charges and a rapid chromatin decompaction or expansion and subsequent nuclear bursting or expulsion. The resulting extracellular DNA-protein complex is enriched in ligands for receptor for advanced glycation endproducts (RAGE). The chromatin-bound RAGE ligand S100a4 activates RAGE receptors in neighboring surviving tumor cells, leading to Erk activation and metastatic outgrowth.

Most tumor cells undergo apoptosis in circulation and at the metastatic organsites due to host immune surveillance as well as therapeutic treatment. Tumor cells are also highly heterogeneous, exhibiting diverse responses when exposed to different environments. Our studies reveal a mechanism of tumor heterogeneity in apoptosis by which some tumor cells die for the benefits of the population’s survival through Padi4-mediated nuclear expulsion.