Abstract B082: Oncogenic KRAS-mediated epigenetic reprogramming is altered by loss of Activating Transcription Factor 3
Bibliographic record
Abstract
Abstract Introduction: Over 90% of PDAC patients harbor an activating KRAS mutation, the most common form being KRASG12D. However, additional genetic mutations and environmental events, including chronic or hereditary pancreatitis, are needed for KRAS mutations to lead to PDAC. Our laboratory showed Activating Transcription Factor 3 (ATF3) was required for repressing genes that stabilize the mature acinar cell phenotype and for KRASG12D-driven progression to advanced PanIN lesions. However, ATF3 contributes to gene activation and repression and has been linked to numerous transcription factors and epigenetic mediators, and how ATF3 affects PDAC progression remains unknown. We hypothesize that KRASG12D promotes ATF3-driven histone acetylation in precursor PanINs lesions. Methods: C57Bl/6l mice allowing for acinar-inducible KRASG12D combined with (Ptf1acreERTKRASG12D) or without (Ptf1acreERTKRASG12DAtf3-/-; APK) Atf3 deletion were treated with tamoxifen to induce KRASG12D. After 10 days, mice were treated with cerulein to induce injury and PanIN progression. Mice were sacrificed after two weeks and 3D organoid lines developed. RNA-seq and chromatin immunoprecipitation for H3K27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) was performed. Bioinformatic analysis was used to identify differentially enriched pathways. Levels of acetyl-CoA, the substrate for acetylation, was compared between lines along with levels of H3K27ac, H3K4me1, H3K4me3, and H3K9me3 through western blots. Results and Discussion: KRASG12D expression promoted epigenetic reprogramming in PanINs, including dysregulation of H3K27ac enrichment. ChIP-seq results showed the absence of ATF3 reduces H3K27 acetylation preferentially at gene promoters and pathway analysis showed differential enrichment and activation of KRAS signaling. Mechanistically, ATF3-deleted mice have lower acetyl-CoA levels, linking ATF3 to metabolic pathways as a possible mechanism for gene regulation. Comparing genes with an ATF3-dependent acetylation pattern to a curated list of KRAS-targeted genes identified SMARCC2 (BAF170), a SWI/SNF complex subunit, and KDM1B, a histone demethylase affecting H3K4, suggesting a potential role for ATF3 in widespread epigenetic regulation. Public sequencing data from PDAC patients, supports these findings as ATF3 expression is positively correlated with expression of several SWI/SNF complex subunits and demethylases. Conclusion: This study highlights a role for ATF3- mediated epigenetic dysregulatio. In oncogenic KRAS-dependent PDAC. Targeting this ATF3- mediated epigenetic landscape could be a promising new therapeutic avenue. Citation Format: Fatemeh Mousavi, Christopher L Pin, Parisa Shooshtari. Oncogenic KRAS-mediated epigenetic reprogramming is altered by loss of Activating Transcription Factor 3 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B082.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".