How tumour cells in pancreatic ductal adenocarcinoma (PDAC) evade digestion by secreted pancreatic enzymes remains unclear. Lv and colleagues show that in PDAC cells, the pore forming protein gasdermin E (GSDME) promotes the production of mucin 1 (MUC1) and mucin 13 (MUC13) (key components of the protective mucous layer of pancreatic epithelia) by transporting the transcription factor YBX1 to the nucleus, revealing that GSDME protects PDAC from digestion. As GSDME expression levels are high in human PDAC cell lines, the authors knocked down GSDME with single guide RNAs (GSDME-SG) in human PDAC cells; GSDME-SG cells were sensitized to the cytotoxic action of the pancreatic enzymes trypsin and chymotrypsin, indicating that GSDME is required for PDAC cells to resist digestion. In addition, the expression of MUC1 and MUC13 was reduced in GSDME-SG cells, which led to impaired resistance to digestive enzymes in vitro and delayed tumour growth in orthotopic transplants of GSDME-SG cells in mice. Expression of exogenous MUC1 and MUC13 in GSDME-SG cells rescued both phenotypes. Thus, GSDME seems to promote resistance to digestion by inducing MUC1 and MUC13 expression.
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