Abstract 2732: The role of Cdx transcription factors in intestinal tumorigenesis.
Bibliographic record
Abstract
Abstract Mutations in the Adenomatous polyposis coli (APC) gene are an early causative event in human colorectal cancer (CRC). The Min mouse, which harbors mutations of APC, is a widely used model for CRC, although it presents with benign polyps restricted largely to the small intestine. The transcription factors Cdx1 and Cdx2 are expressed throughout the intestinal epithelium from early gut development, and persist throughout the life of the animal. Cdx1 null mice exhibit no intestinal phenotype while Cdx2 null mice die around embryonic day 3.5. Cdx2 heterozygotes, however, have an intestinal phenotype characterized by lesions in the pericaecal region and proximal colon suggestive of a role for Cdx2 in posteriorizing the intestinal tract. Consistent with this, recent studies using conditional knockout approaches show loss of Cdx2 from the developing or adult intestinal epithelium results in an anteriorized intestinal phenotype. Cdx2 loss has been detected in 30% of human CRC, and Cdx2 heterozygous-APC mutants exhibit an increase in polyp formation in the colon; similar results are seen with Cdx2 heterozygotes treated with the carcinogen azoxymethane. These studies suggest that Cdx2 has tumor suppressor properties, however the mechanism by which Cdx2 elicits this effect is unknown. We are using a Cre-lox system to conditionally delete Cdx2 from the adult intestine alone or in a heterozygous Min background. The tamoxifen-regulated Cre, under the spatial control of the villin promoter, is fused to a modified estrogen receptor ligand binding domain that responds only to tamoxifen. Sub-optimal tamoxifen treatment is used to effect partial loss of Cdx2 to circumvent the lethality inherent to Cdx2 loss in the adult intestine. Animals will be sacrificed commencing at 14 weeks post-treatment for analysis of intestinal lesions and compound mutants will be compared to mice deficient for Cdx2 or Min alone. Partial tamoxifen treatment was successful at yielding mice with chimeric loss of Cdx2. In contrast to germ-line Cdx2 heterozygotes, chimeric Cdx2 deletion did not produce hamartomas. In contrast, Cdx-Min compound mutants exhibited a faster trajectory of wasting compared to Min heterozygotes, necessitating endpointing by 14 weeks post-treatment. These compound mutant mice exhibited a three-fold increase in tumor incidence compared to Min controls, with an increased tumors size. Histologically, the small intestinal tumors that developed in the Cdx-Min background have an altered histological appearance compared to the adenomatous Min tumors. Proliferative cells and nuclear beta-catenin expression, seen within the Min tumors, were expanded in the Cdx-Min tumors, consistent with activation of the Wnt pathway in both tumor types. This work illustrates that the conditional Cdx2 allele is an effective tool for studying the role of this transcription factor in the adult intestine, and reaffirms an important role for Cdx2 in the genesis of intestinal cancers. Citation Format: Alexa Hryniuk, David Lohnes, Stephanie Grainger. The role of Cdx transcription factors in intestinal tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2732. doi:10.1158/1538-7445.AM2013-2732
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".