Gasdermin E mediates resistance of pancreatic adenocarcinoma to enzymatic digestion through a YBX1-mucin pathway

Pancreatic ductal adenocarcinoma (PDAC) originates from normal pancreatic ducts where digestive juice is regularly produced. It remains unclear how PDAC can escape auto-digestion by digestive enzymes. Here we show that human PDAC tumor cells use gasdermin E (GSDME), a pore-forming protein upon caspase 3 cleavage, to mediate the digestive resistance. We find that GSDME facilitates the expression of mucins 1 and 13 in pancreatic tumor cells, which forms a barrier to prevent chymotrypsin-mediated destruction. Inoculation of GSDME-/- PDAC cells results in subcutaneous but not orthotopic tumor formation in mice. Either inhibiting or knocking out MUC1 or MUC13 abrogates orthotopic PDAC growth in NOD-SCID mice. Mechanistically, GSDME interacts with and transports transcription factor YBX1 into the nucleus where YBX1 directly promotes mucin expression. This GSDME-YBX1-mucin axis is also confirmed in PDAC patients. These findings uncover a unique survival mechanism of PDAC cells in pancreatic microenvironments, thus providing a potential target for PDAC treatment.