A284 ROLE OF KRT15+ STEM CELLS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Bibliographic record
Abstract
In Canada, patients with esophageal cancer have a 5-year survival rate of only 14%, the 2nd worst in 2017. Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer worldwide. Risk factors include tobacco smoking, alcohol use and esophagitis. Esophagitis is developed upon several insults (e.g. acid/bile reflux, radiation, infection). Epithelial damages typically trigger activation of stem cells which will orchestrate tissue regeneration. The existence of esophageal stem cells remained controversial until our studies. We recently identified that Krt15 promotor marks a subpopulation of esophageal basal cells which display self-renewal and multipotent capacities, characteristics consistent with a stem cell population. Our preliminary results suggest that Krt15 esophageal cells have tumor-initiating capacities in mouse. However, we still ignore the role of these cells at later stages of the disease. Cancer stem cells (CSCs) have been linked to treatment resistance and poor survival rate. Therefore, the characterization of esophageal CSCs is a promising strategy to improve survival and treatment in ESCC patients. The aim of this study is to investigate the role of Krt15+ esophageal cancer cells in cancer initiation, progression and relapse. We hypothesize that Krt15+ cells initiate tumor formation and contribute to the establishment of treatment resistance in ESCC patients. The carcinogen 4-nitroquinoline 1-ozide (4NQO) is used to induce oral-esophageal lesions in mouse that morphologically resemble human ESCC. Krt15-CrePR1;Rosa26mTomato/mGFP mice are treated with 4-NQO in the drinking water and expansion of Krt15+ (GFP-labeled) cells was measured. To determine the role of Krt15+ cells in esophageal tumor initiation, we treated Krt15-CrePR1;Rosa26mTomato/mGFP mice with 4-NQO. We observed that Krt15+ cells expand in the esophageal lesions. The clones formed by Krt15+ cells (GFP-labeled) were bigger in mice treated with 4-NQO than in control mice suggesting that Krt15+ cells contribute to ESCC expansion. Interestingly, in human ESCC tumors, we observed that K15 expression is localized at the tumor migration edges suggesting a role for K15 in migration and invasion. Furthermore, we isolated esophageal tumors from WT mice treated with 4-NQO. We observed that K15 expression is also increased in the invasive front of mouse esophageal tumors. Finally, we quantified the expression of Krt15 transcript in mouse ESCC cell lines which harbor variable tumorigenicity and aggressiveness. We observed that Krt15 expression correlated with the aggressiveness of ESCC mouse cell lines. Our results support that Krt15+ stem cells play a role in ESCC initiation and progression suggesting that targeting these stem cells might be a therapeutic approach to improve survival of ESCC patients. Start-up funding (Université de Sherbrooke and CRCHUS)
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".