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Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer.

Nature communications

Authors: Yu C J Chey, Bassam Kashgari, Louise McLeod, Georgette A Radford, Linden J Gearing, Ruby E Dawson, Malvika Kharbanda, Joanne Lundy, Daniel Croagh, Charlotte Girard-Guyonvarc'h, Cem Gabay, Brooke A Pereira, David Herrmann, Paul Timpson, John W Finnie, Mohamed I Saad, Dharmesh D Bhuva, Bernardo S Franklin, Florian I Schmidt, Brendan J Jenkins

Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our discovery that ASC-containing inflammasomes promote PDAC by acting as a molecular bridge between innate immunity, mitochondrial dysfunction and metabolic reprogramming provides the rationale to therapeutically target ASC in cancers.

© 2026. The Author(s).

PMID: 41654528

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