The Id3/E47 Axis Mediates Cell-Cycle Control in Human Pancreatic Ducts and Adenocarcinoma
Bibliographic record
Abstract
Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5%, and therapeutic advances have been hampered by gaps in our understanding of cell-cycle control in the adult pancreas. Previously, we reported that basic Helix-Loop-Helix (bHLH) transcription factors regulate cell fate specification in the pancreas. In the present study, we found that a repressor of bHLH activity, Id3, was profoundly upregulated in ductal cells in murine models of pancreatitis and pancreatic intraepithelial neoplasia (PanIN). Id3 was also pervasively expressed in neoplastic lesions in human PDA in situ. We hypothesized that an imbalance in bHLH versus Id activity controlled cell growth in PDA. Consistent with this model, cell-cycle progression in PDA cells was impeded by siRNA-mediated depletion of Id3 or overexpression of the bHLH protein E47. The precursors of human PDA are normally quiescent duct cells which do not proliferate in response to high serum or growth factors. The finding that Id3 was expressed in pancreatitis, as well as PDA, suggested that Id3 might induce cell-cycle entry in ducts. To test this hypothesis, primary human pancreatic duct cells were transduced with an adenovirus-expressing Id3. Remarkably, Id3 expression alone was sufficient to trigger efficient cell-cycle entry, as manifested by expression of the proliferation markers Ki67, phospho-cyclin E, and phospho-histone H3. Collectively, the data establish dysregulation of the Id/bHLH axis as an early and sustained feature of ductal pathogenesis and mark this axis as a potential therapeutic target for intervention in pancreatitis and PDA.
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How this classification was reachedexpand
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 | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".