Acinar-specific loss of activating transcription factor 3 restricts KRASG12D mediated transcriptional changes and PanIN progression
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Bibliographic record
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in North America with ~12% survival 5 years after diagnosis. Risk factors for PDAC, including smoking and chronic pancreatitis, trigger the unfolded protein response (UPR). Global deletion of Activating Transcription Factor 3 (ATF3), a UPR mediator, restricts preneoplastic progression in mice expressing oncogenic KRAS (KRAS G12D ). However, ATF3 is expressed in malignant and non-malignant cells suggesting it may affect multiple cell compartments in PDAC. Therefore, the goal of this study was to determine if ATF3 has epithelial-specific roles during PDAC initiation. Epithelial cells from mice expressing KRAS G12D with ( Ptf1a creERT/+ KRAS G12D /+ ) or without ATF3 ( Atf3 −/− Ptf1a creERT/+ KRAS G12D/+ ; APK ) were characterized before and after pancreatic injury. Additionally, mice allowing acinar-specific Atf3 deletion and KRAS G12D expression ( A acinar PK ) were compared to Ptf1a creERT/+ KRAS G12D /+ and APK mice following injury. RNA-seq revealed reduced oncogenic pathways in APK acinar cells consistent with reduced ADM formation in APK cultures. Ptf1a creERT/+ KRAS G12D /+ and APK organoids showed differential gene expression and morphology, with APK organoids exhibiting reduced viability. In vivo, APK and A acinar PK tissue showed restricted neoplastic progression and KRAS signaling compared to Ptf1a creERT/+ KRAS G12D /+ mice. This study indicates ATF3 works in a cell autonomous fashion, and its absence restricts KRAS G12D -mediated PDAC.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it