Determining the mutational burden of tumor cells that survive apoptotic caspase activation in the presence or absence of Gasdermin E
Recent studies have described an ability of cancer cells to survive engagement of apoptotic pathways following chemical and therapeutic insults, challenging the prevailing model that caspase activation inevitably led to cellular demise. Gasdermin E (GSDME), whose expression is frequently downregulated or silenced in many tumor-derived cell lines, was proposed as a putative tumor suppressor, although its mechanism of action remains unclear. We found that GSDME expression precluded high caspase activity prior to cellular membrane rupture downstream of chemical and immune-mediated insults, and its absence allowed for enhanced activities downstream of caspase activation, including the DNA-damaging effects of Caspase Activated DNase (CAD). Loss of GSDME allowed cells that had sustained DNA damage to survive, resulting in development and propagation of mutated clones. We conclude that GSDME functions as a key rheostat for determining cell death outcomes by tuning the tolerance to the activities of caspases and their substrates during apoptosis. One consequence may be the accumulation of mutations in tumors with low GSDME expression and high immune signatures, supported by analysis of TCGA data.
Recent studies have described an ability of cancer cells to survive engagement of apoptotic pathways following chemical and therapeutic insults, challenging the prevailing model that caspase activation inevitably led to cellular demise. Gasdermin E (GSDME), whose expression is frequently downregulated or silenced in many tumor-derived cell lines, was proposed as a putative tumor suppressor, although its mechanism of action remains unclear. We found that GSDME expression precluded high caspase activity prior to cellular membrane rupture downstream of chemical and immune-mediated insults, and its absence allowed for enhanced activities downstream of caspase activation, including the DNA-damaging effects of Caspase Activated DNase (CAD). Loss of GSDME allowed cells that had sustained DNA damage to survive, resulting in development and propagation of mutated clones. We conclude that GSDME functions as a key rheostat for determining cell death outcomes by tuning the tolerance to the activities of caspases and their substrates during apoptosis. One consequence may be the accumulation of mutations in tumors with low GSDME expression and high immune signatures, supported by analysis of TCGA data.
St Jude Children's Research Hospital