Failed apoptosis enhances melanoma cancer cells aggressiveness

Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination, since cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, though it remains unclear how failed apoptosis impacts established cancers. Using a cancer cell model to trigger non-lethal caspase activation based on either BH3-only protein expression or chemotherapy treatment, we found that melanoma cancer cells failing to undergo complete apoptosis have a particular transcriptomic signature associated with focal adhesions, transendothelial migration and modifications of actin cytoskeleton. In line with this, cancer cells surviving apoptosis have a gain in migratory and invasive properties both in vitro (random migration, chemotaxis, wound healing and invasion assays) and in vivo (in a model of zebrafish metastasis) We further demonstrate that the failed apoptosis-associated gain in invasiveness is regulated by the c-Jun N-terminal kinase (JNK) pathway while its RNA seq signature is found in metastatic melanoma. These findings are highly significant for understanding how cell death can both cure and promote cancer.