ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway
Bibliographic record
Abstract
Abstract The unfolded protein response maintains endoplasmic reticulum homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the endoplasmic reticulum transmembrane proteins IRE1, PERK, and ATF6. Malignant cells can co-opt IRE1 and PERK to sustain growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers, including colorectal carcinoma. Genetic silencing or small-molecule inhibition of ATF6 blocked cell-cycle progression and reduced viability of several human colorectal cancer cell lines in vitro, and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference disabled Wnt and Myc signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, decreasing Wnt pathway activity and driving cellular differentiation. Wnt-surrogate agonism in a Wnt ligand-dependent colorectal cancer organoid restored pathway activity and rescued growth under ATF6 blockade. Our findings uncover ATF6 as an unexpected facilitator of oncogenic Wnt signaling in colorectal cancer. Significance: ATF6 intervention reduces colorectal cancer cell and organoid viability by interrupting dysregulated Wnt signaling, identifying a novel facilitator and potential therapeutic target in colorectal cancer.
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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 | 0.000 | 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 | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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".