A246 ROLE OF DOUBLECORTIN-LIKE KINASE 1 (DCLK1) POSITIVE TUFT CELLS IN COLITIS-ASSOCIATED COLORECTAL CANCER
Bibliographic record
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death in Canada, with the major risk factor being chronic inflammation. How inflammation leads to cancer is not well understood. Our recent work has focused on a colonic epithelial cell known as the tuft cell that uniquely expresses the protein doublecortin-like kinase 1 (Dclk1). Using Cre-dependent lineage tracing of Dclk1-expressing cells, we showed that Dclk1 labels long-lived quiescent cells in the colon that serve as a cellular origin of CRC upon inflammatory injury. The aim of the study was to determine the generalizability of inflammation-induced tumor promotion from genetically susceptible Dclk1+ cells and explore the mechanism by which inflammation contributes to tuft cell cancer initiation. We hypothesized that various colonic inflammatory insults lead to dedifferentiation of Dclk1+ tuft cells to a stem cell state susceptible to tumor initiation. To investigate the various forms of injury or infection that can activate quiescent tuft cells, we crossed our transgenic Dclk1-CreERT2 mice to both ROSA26-tdTomato and APCf/f mice (Dclk1/APCf/f). Following tamoxifen induction, mice were treated with the colitis-inducing agents dextran sodium sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), oxazolone or Citrobacter rodentium. To examine the role of dedifferentiation in colonic tumor initiation, we crossed Lgr5-DTR-eGFP mice to our Dclk1/APCf/f mice. The mice were then given tamoxifen and DSS to induce tumorigenesis and diphtheria toxin (DT) post DSS injury to ablate Lgr5+ intestinal stem cells. Treatment with DSS, TNBS, oxazolone, or C. rodentium induced colonic inflammation as detected by significantly increased myeloperoxidase (MPO) activity and histologic analysis. DSS administration led to Dclk1+ cell-derived colonic tumors as previously reported. Surprisingly, administration of TNBS, oxazolone, or C. rodentium in Dclk1/APCf/f mice did not lead to colonic tumorigenesis up to 52 weeks following induction of colitis. Interestingly, ablation of Lgr5+ intestinal stem cells post colitis significantly reduced colonic tumors in DSS-treated Lgr5-DTR-eGFP/Dclk1/APCf/f mice. Our data suggests that a specific inflammatory response unique to DSS-induced colitis, and not TNBS, oxazolone or C. rodentium infection, results in colonic tumor formation. Interestingly, the colonic transformation of Dclk1+ tuft cells in DSS colitis appears to be mediated through Lgr5-expressing cells. These findings provide insight into the molecular pathways by which Dclk1-derived colonic tumors arise. CAG, CIHRCFI
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".