Anastasis confers ovarian cancer cells increased malignancy through elevated p38 MAPK activation

Activation of executioner caspases was once considered as a point of no return in apoptosis. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process called anastasis. In this study, we developed a reporter system, mCasExpress, to track mammalian cells that survive executioner caspase activation. We demonstrate that anastatic ovarian cancer cells acquire enhanced migration following their transient exposure to apoptotic stimulus TRAIL or Paclitaxel. Moreover, anastatic cancer cells secrete more pro-angiogenic factors that enable tumor angiogenesis, growth and metastasis. Mechanistically, we demonstrate that activation of p38 MAPK, which occurs in a caspase-dependent manner in response to apoptotic stress to promote anastasis, persists at a higher level in anastatic cancer cells even after removal of apoptotic stimuli. Importantly, p38 is essential for the elevated migratory and angiogenic capacity in the anastatic cells. Our work unveils anastasis as a potential driver of tumor angiogenesis and metastasis.