Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yabo Zhou

LAB HEAD: Bo Huang

PROVIDER: PXD030879 | Pride | 2022-05-20

REPOSITORIES: Pride

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

Lv Jiadi J Liu Yuying Y Mo Siqi S Zhou Yabo Y Chen Fengye F Cheng Feiran F Li Cong C Saimi Dilizhatai D Liu Mengyu M Zhang Huafeng H Tang Ke K Ma Jingwei J Wang Zhenfeng Z Zhu Qiangqiang Q Tong Wei-Min WM Huang Bo B

Nature cell biology 20220315 3

Pancreatic ductal adenocarcinoma (PDAC) originates from normal pancreatic ducts where digestive juice is regularly produced. It remains unclear how PDAC can escape autodigestion by digestive enzymes. Here we show that human PDAC tumour cells use gasdermin E (GSDME), a pore-forming protein, to mediate digestive resistance. GSDME facilitates the tumour cells to express mucin 1 and mucin 13, which form a barrier to prevent chymotrypsin-mediated destruction. Inoculation of GSDME<sup>-/-</sup> PDAC c ...[more]

PMID: 35292781

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