ALDH1A3 is the switch that determines the balance of ALDH+ and CD24−CD44+ cancer stem cells, EMT-MET, and glucose metabolism in breast cancer
Bibliographic record
Abstract
Abstract Plasticity is an inherent feature of cancer stem cells (CSCs) and regulates the balance of key processes required at different stages of breast cancer progression, including epithelial-to-mesenchymal transition (EMT) versus mesenchymal-to-epithelial transition (MET), and glycolysis versus oxidative phosphorylation. Understanding the key factors that regulate the switch between these processes could lead to novel therapeutic strategies that limit tumor progression. We found that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates these cancer-promoting processes and the abundance of the two distinct breast CSC populations defined by high ALDH activity and CD24 − CD44 + cell surface expression. While ALDH1A3 increases ALDH + breast cancer cells, it inversely suppresses the CD24 − CD44 + population by retinoic acid signaling-mediated gene expression changes. This switch in CSC populations induced by ALDH1A3 was paired with decreased migration but increased invasion and an intermediate EMT phenotype. We also demonstrate that ALDH1A3 increases oxidative phosphorylation and decreases glycolysis and reactive oxygen species (ROS). The effects of ALDH1A3 reduction were countered with the glycolysis inhibitor 2-deoxy-D-glucose (2DG). In cell culture and tumor xenograft models, 2DG suppresses the increase in the CD24 − CD44 + population and ROS induced by ALDH1A3 knockdown. Combined inhibition of ALDH1A3 and glycolysis best reduces breast tumor growth and tumor-initiating cells, suggesting that the combination of targeting ALDH1A3 and glycolysis has therapeutic potential for limiting CSCs and tumor progression. Together, these findings identify ALDH1A3 as a key regulator of processes required for breast cancer progression and depletion of ALDH1A3 makes breast cancer cells more susceptible to glycolysis inhibition.
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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 | 0.000 | 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".