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<p>Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., <i>KRAS</i>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • 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

摘要

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.