Caspase 8 protects pancreatic neoplasia from KRAS-driven necroptotic priming

Abstract Caspase 8 regulates normal tissue homeostasis by executing apoptosis and protecting from necroptosis. Several aggressive cancers express high levels of caspase 8, yet its function in neoplastic disease remains poorly explored. Here, we find that oncogenic KRAS-driven neoplastic transformation induces a transcriptional state of necroptotic priming, but necroptosis itself is kept in check by co-upregulation of caspase 8. Mice in which caspase 8 is deleted in the pancreas manifested a drastic decrease in precursor lesion formation in a KRASG12D-driven model of pancreatic cancer. Co-deletion of the essential necroptosis effector MLKL reversed the protective effects of caspase 8 ablation, and promoted metastasis. Mechanistically, oncogenic KRAS induced a STING-dependent type I interferon response, resulting in upregulation of necroptosis pathway components. High caspase 8 expression in precursor lesions was a result of co-selection to prevent necroptosis. Therefore, triggering necroptosis by blocking caspase 8 activity was therapeutically highly efficacious in models of genetically engineered PDAC in vivo. These results assign a tumor-protective function to caspase 8 in PDAC and show that overcoming caspase 8 activity has therapeutic benefit in this incurable malignancy.