Abstract PO-017: Targeting murine oral tumors by pharmacological inhibition of b-catenin/CBP epigenetic activity
Bibliographic record
Abstract
Abstract In previous studies, we have shown that pharmacological blockade of Wnt/β-catenin/CBP activity with small molecule inhibitors is effective in abolishing oncogenic phenotypes in oral squamous cell carcinoma (OSCC). To further characterize changes in Wnt/β-catenin activity during malignant transformation, we used an immunocompetent mouse model of oral cancer induced by a tobacco-derived carcinogen, 4-nitroquinoline-1-oxide (4NQO), which recapitulates the human OSCC mutational landscape and tumor immune environment. We performed single-cell RNA sequencing (scRNAseq) on tongue tissues from healthy mice (n=2), 4NQO-derived mouse OSCC (n=2), and from 4NQO-derived mouse OSCC treated with a pharmacologic grade 𝛽-catenin/CBP inhibitor (n=2). The experiment yielded ~50K cells across all conditions and identified multiple cell types and states, including epithelial and immune cells, as well as endothelia, fibroblasts, and glial cells. We found significant cellular composition changes between 4NQO and 4NQO inhibitor-treated groups, with the proportion of epithelial cells decreasing upon treatment with the 𝛽-catenin/CBP inhibitor, and the endothelial and fibroblast populations increasing in the 𝛽-catenin/CBP inhibitor group. Analysis within the immune compartment showed significant cell type proportion changes between the 4NQO and 4NQO inhibitor-treated groups, including changes in neutrophils population decreasing upon treatment to inhibitor, macrophages, and DCs increasing in the treatment group, along with T- and B-cells. ~50% of the cellular composition in each group comprised of neutrophil population. Further subtyping of the neutrophil population into early and late “neutrotime” subclasses based on published signatures showed enrichment of the early neutrotime class in the inhibitor-treated group and of the late neutrotime class in the 4NQO group. Analysis within the epithelial compartment identified several cell type proportions, including basal (Krt5+, Krt15+), proliferating (Krt5+, Krt14+), and cycling (Top2a, Cdc20) cells increased upon treatment with the inhibitor, and acinar cell-types (Muc5b, Aqp5, Smgc) decreasing upon treatment in comparison with the 4NQO group. The inhibitor-treated group also showed lower proportions of malignant transforming cell states compared to the 4NQO group. A cell-cell communication analysis was performed between epithelial and immune compartments to identify ligand-receptor (LR) interactions indicative of treatment response. Among the significant interactions, the LRs related to collagen organization (Cdh1, Icam1, Lamc1) and major histocompatibility complex genes such as H2-d1, H2-k1, H2-q4, etc., were enriched in the treatment group indicating cellular plasticity and immune regulation processes in comparison with the 4NQO group. Taken together, our results indicate mitigation of cellular heterogeneity and plasticity profiles in 4NQO-induced tumors upon treatment with 𝛽-catenin/CBP inhibitor in OSCC. Citation Format: Mohammed Muzamil Khan, Eric Reed, Lina Kroehling, Manish Bais, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti. Targeting murine oral tumors by pharmacological inhibition of b-catenin/CBP epigenetic activity [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-017.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".