Loss of Sox10 prevents tumor initiation and induces luminal-to-basal reprograming in a HER2+ mouse model
Bibliographic record
Abstract
Abstract The SRY-HMG-Box transcription factor SOX10 plays a critical role in neural crest development, but its function in epithelial tumorigenesis remains unclear. Here, we identify SOX10 as a key regulator of tumor-initiating activity in Neu-driven mammary cancers. Genetic ablation of Sox10 in the luminal compartment of MMTV-Neu (NIC) mice resulted in delayed but normal mammary gland development. Sox10 deletion resulted in a reduction in mammary progenitors and tumor initiating activity with a complete loss of tumor initiation in Sox10-deficient luminal cells. CRISPR/Cas9-mediated Sox10 inactivation in Neu-transformed tumor cells led to diminished self-renewal in mammosphere assays, markedly impaired growth in orthotopic transplant models and profoundly reduced lung colonization following tail vein injection, suggesting a depletion of cancer stem cell activity. Transcriptomic profiling revealed that Sox10-deficiency in Neu+ tumor cells induces a luminal-to-basal/stem-like shift and the downregulation of several genes associated with genetic networks regulating stemness. Collectively, these findings demonstrate that Sox10 is required for a permissive luminal cell state for Neu-driven tumor initiation and that it is critical for cancer stem cell activity and the establishment of metastases. Significance The Sox10 transcription factor is critical for mammary stem cell function and plasticity. Animal studies suggest that different subtypes of breast cancers arise from luminal epithelial cells and hypothesized the implication of luminal stem cells in breast cancer initiation. We show that Sox10 deletion in the luminal compartment of adult female mice abrogates tumor initiation. Sox10 inactivation impairs tumor cell growth, dissemination and reprograms luminal Neu+ tumor cells to a basal phenotype. Our data supports a model whereby luminal progenitors are required for tumor initiation, self-renewal and growth at distant sites. The findings suggest that therapies aimed at interfering with Sox10 activity or expression might be beneficial in the treatment of breast cancers.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".