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Updated: Jun 23, 2025
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Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
Published on: February 11, 2019
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KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis
Ashley N Sigafoos1, Ezequiel J Tolosa1, Ryan M Carr1,2
1Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
Cancer Research Communications
|June 19, 2024
Summary
Aberrant GLI2 activation accelerates pancreatic cancer by interacting with KRAS. This interaction boosts oncogenic gene expression, leading to faster tumor growth and reduced survival in a novel mouse model.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant GLI transcription factors are linked to various cancers.
- The precise mechanisms connecting GLI factors to pancreatic ductal adenocarcinoma drivers like KRAS are not fully understood.
Purpose of the Study:
- To investigate the interplay between KRAS and GLI2 in pancreatic ductal adenocarcinoma pathogenesis.
- To elucidate the molecular mechanisms by which KRAS and GLI2 cooperate to drive oncogenic gene expression.
Main Methods:
- Utilized a novel genetically engineered mouse model co-expressing active GLI2 and KrasG12D.
- Employed RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) for genome-wide analysis.
- Performed GLI2 knockdown experiments to assess functional impact.
Main Results:
- Mice with both KrasG12D and active GLI2 exhibited accelerated tumorigenesis and reduced survival.
- KrasG12D significantly upregulated GLI2 target genes, including Ccnd1, N-Myc, and Bcl2.
- KrasG12D enhanced H3K4me3 marks at GLI2 target promoters, a process dependent on GLI2 activity.
Conclusions:
- GLI2 acts as a downstream effector of KRAS signaling in pancreatic cancer.
- The KRAS-GLI2 axis promotes oncogenic gene expression through epigenetic modifications like H3K4me3 enrichment.
- Targeting GLI2 may offer a therapeutic strategy for KRAS-driven pancreatic ductal adenocarcinoma.
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