A31 ALTERED SMALL INTESTINAL EPITHELIAL HOMEOSTASIS AND CELL FATE DECISION UPON LOSS OF TRP53 IN KRT15+ INTESTINAL STEM CELLS
Bibliographic record
Abstract
Abstract Background Intestinal homeostasis is mainly maintained by two groups of stem cells: Lgr5+ stem cells and reserve stem cells. Recently, we reported that Krt15+ cells are present in small intestinal and colon epithelia, and harbor self-renewal, multipotent and regenerative capacities. Initiation of sporadic colorectal cancer has been described in Krt15+ stem cells, Lgr5+ stem cells and reserve stem cells following the loss of Apc. While these intestinal stem cell (ISC) populations can act as tumor-initiating cells in sporadic colon cancer, little is known about the cell-of-origin of colitis-associated colon cancer. TP53 alteration is reported as an early event in colitis-associated colon cancer cases. Therefore, we hypothesize that Trp53 loss specifically in Krt15+ stem cells will perturb the epithelial homeostasis and lead to tumor formation Aims Identify if Krt15+ cells may act as the cell-of-origin in colitis-associated colorectal cancer. Methods To induce Trp53 loss specifically in Krt15+ cells, we generated Krt15-CrePR1;Trp53fl/fl (Krt15△Trp53) mice, induced Cre recombination by injecting RU486 (PR agonist) and euthanized the mice after 12 months following recombination. Histological analysis was performed on small intestinal tissues. Results Results: Trp53 loss in Krt15+ cells severely perturbed small intestinal morphology. Increased crypt (proliferative compartment) length correlated with no proliferation changes surprisingly but higher number of Paneth cells and abnormal presence of goblet cells. Interestingly, we also observed the presence of cells expressing both Paneth and goblet cells markers suggesting a deregulation of secretory cell fate decision. Decreased expression of Hes1 and increased β-catenin nuclear expression in the small intestinal crypt of Krt15△Trp53 mice suggest altered Notch and Wnt signaling. Furthermore, villi (differentiated compartment) were significantly wider and shorter, and showed accumulation of activated fibroblasts. Finally, we observed inflammatory lesions as well as adenomas in the small intestine of Krt15△Trp53 mice which remain to be further characterized Conclusions Conclusion: In summary, Trp53 loss specifically in Krt15+ cells impaired cell fate decision, induced inflammation and initiated tumor formation. Overall, these results suggest that Krt15+ cells could act as the cell-of-origin of colitis-associated colon cancer. Funding Agencies Cancer Research Society, CRC Tier 2
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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".