Abstract 2307: Cellular expression of E-cadherin but not its plasma membrane localization is regulated by the PTEN/PI 3 Kinase pathway via transcription factors twist and snail
Bibliographic record
Abstract
Abstract Introduction: 90% of carcinoma-related deaths in adults and children are associated with cancer metastasis. Metastasis involves phenotypical changes in cancer cells within the primary tumor. To acquire motility and invasiveness, carcinoma cells must shed many epithelial phenotypes, detach from neighboring cells and undergo a series of drastic alterations commonly referred to as the “Epithelial-Mesenchymal Transition (EMT)”. In normal epithelium, E-cadherin expression provides high-affinity anchoring to neighboring cells, serving as a tumor suppressor mechanism. With malignant transformation, N-cadherin is upregulated. Results: Using a panel of cell lines representing the various stages of melanoma progression, [primary melanocytes (HEMA-LP); radial (WM 35); vertical (WM793) and metastatic (A2058) growth phases], we have confirmed a switch in cadherin phenotype from E- to N-cadherin. The greatest expression of E-cadherin is evident in the HEMA-LP cell line, with null expression in A2058. N-cadherin is expressed abundantly in WM793 and A2058, with almost null expression in Hema-LP. Interestingly, there is also a loss of expression of the tumor suppressor PTEN in WM793 and A2058. Transfection of wild type PTEN in A2058 cells resulted in re-expression of E-cadherin and a drop in N-cadherin levels. We also determined that the PTEN-modulated switch in cadherin profile is regulated at the transcriptional level, and involves the transcription factors Twist and Snail. Cellular expression of Twist and Snail was greatest in A2058 cells and lowest in HEMA-LP cells. Transfection of PTEN into A2058 cells caused a decrease in expression of Twist and Snail. Further, targeted knockout of Twist with shRNA in A2058 cells resulted in suppression of N-cadherin expression and the appearance of E-cadherin, while transfection of a Twist over-expression vector in HEMA-LP resulted in suppression of E-cadherin expression and the appearance of N-cadherin. Surprisingly, the invasive capacity of the A2058 cells was only reduced by 40% in the presence of PTEN. Immunofluorecent analysis of E-cadherin expression in A2058 cells indicated that this may be due to the fact that the re-expressed E-cadherin does not become targeted and localized to the plasma membrane. Conclusion: We define a pathway that regulates cellular E- & N-cadherin expression modulated at the transcriptional level by the PTEN/PI-3 Kinase pathway and involves the transcription factors twist and snail. However, the targeted localization of E-cadherin to the plasma membrane is not regulated by this pathway but by other mechanism(s) that have not yet been identified. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2307.
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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".