Abstract A054: Activating transcription factor 3 promotes KRAS-mediated pancreatic ductal adenocarcinoma
Bibliographic record
Abstract
Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) has ~10% survival 5 years after diagnosis often due to lack of chemotherapeutic response. Unlike many other tumors, pancreatic tumors have a high stromal content and cancer associated fibroblasts (CAFs) play a role in response. To improve patient outcome, we need to determine how tumor and non-tumor cell interactions contribute to PDAC progression. Our laboratory recently showed global deletion of Atf3 in mice expressing oncogenic KRAS (Atf3-/-Ptf1acreERT/+KRASG12D; referred to as APK) reduced preneoplastic lesion progression. However, APK mice also showed increased fibrosis and altered immune cell infiltration and single cell RNA-seq revealed ATF3 expression in tumor and non-tumor cells. These findings suggest ATF3 may affect multiple cell types in PDAC. The goal of this study was to determine the epithelial-specific role ATF3 plays in PDAC initiation. We hypothesize that ATF3 promotes PDAC initiation and progression through epithelial and non-epithelial cell mechanisms. Methods: Mice allowing cre recombinase-inducible KRASG12D activation with (Ptf1acreERT/+KRASG12D) or without Atf3 (APK mice) or combined with Atf3 deletion specific to pancreatic acinar cells (AacinarPK mice) were generated. 2-4 month-old mice from all genotypes were gavaged with tamoxifen to induce cre-mediated recombination. Ten and twelve days following cre activation, pancreatic injury was induced by cerulein. Two weeks post injury, general morphology, tissue histology, and gene expression was compared. In some cases, cells were isolated from pancreatic tissue and prepared for 3-dimensional organoid cultures. Results: Histological analysis indicated AacinarPK mice had fewer high-grade PanIN lesions compared to both APK or Ptf1acreERT/+KRASG12D mice with reduced lesion size, based on the PanIN marker CK19, and pERK accumulation, a downstream mediator of KRAS. In addition, Ptf1acreERT/+KRASG12D, APK, and AacinarPK show differences in stromal makeup. While analysis of the stromal compartment shows no change in overall CAF accumulation, IHC for a-SMA showed reduced accumulation of myCAFs in APK tissue. There is also a reduction in immune cell infiltration when ATF3 is deleted, based on CD45 staining. Analysis of organoid cultures showed loss of ATF3 reduced compact morphology of organoid structures and reduced mesenchymal cell transformation. Conclusion and Future Directions: This analysis supports an epithelial-specific role for ATF3 in KRASG12 -mediated PDAC. Since APK and AacinarPK mice do not show the same phenotype, our data also suggests ATF3 has additional roles in nonepithelial cells. Therefore, cell-specific targeting needs to be considered in treating PDAC. Future experiments will examine ATF3-regulated pathways in the various cell populations found in PDAC. Citation Format: Mickenzie B. Martin, Ye Shen, Christopher Pin. Activating transcription factor 3 promotes KRAS-mediated pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A054.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 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".