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Updated: Mar 29, 2026
08:16
Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
Published on: February 11, 2019
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Mutant KRAS Heterogeneity Shapes Nuclear Architecture During Pancreatic Cancer Initiation
Gareth Pollin1, Angela J Mathison1,2, Elise N Leverence1
1Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Epigenomes
|March 27, 2026
Summary
Different KRAS mutations in pancreatic cancer cells reprogram nuclear structure. G12D causes significant nuclear changes, while G12R has a weaker effect, impacting epigenetic dysregulation in PDAC initiation.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) predominantly arises from KRAS mutations.
- KRAS variants like G12D and G12R exhibit distinct signaling outputs and clinical impacts.
- G12D drives oncogenic programs more strongly than G12R, which is linked to better patient survival.
Purpose of the Study:
- To investigate how different KRAS mutations influence early cellular transformation in PDAC.
- To compare the transcriptional and phospho-proteomic responses to KRAS G12D and G12R variants.
- To determine if epigenetic differences lead to mutation-specific changes in nuclear organization.
Main Methods:
- Expressed KRAS mutants in non-cancerous pancreatic ductal epithelial cells.
- Performed integrated transcriptomic and phospho-proteomic profiling.
- Utilized quantitative imaging to analyze nuclear organization in G12D- and G12R-expressing cells.
Main Results:
- Each KRAS variant established a unique regulatory program, leading to divergent epigenetic states.
- G12D induced significant nuclear remodeling, including increased size and altered nucleolus/spliceosome organization.
- G12R elicited a weaker response with minimal or delayed structural changes compared to G12D.
Conclusions:
- KRAS mutational context shapes early transcriptional reprogramming in pancreatic ductal epithelial cells.
- This reprogramming actively remodels nuclear architecture and sub-compartments.
- Nuclear structural remodeling is a key feature of KRAS-driven epigenetic dysregulation during PDAC initiation.
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