Abstract B147: P-Rex1 is required for efficient melanoma metastasis.
Bibliographic record
Abstract
Abstract Background: P-Rex1 is a Rac-specific Rho GTPase guanine nucleotide exchange factor that has recently been implicated in cancer for the first time. As Rac has a central role in control of cell motility, we assessed the role of P-Rex1 in melanoma, a cancer where metastasis is the major cause of death. This was the first evaluation of P-Rex1 in a genetically modified animal model of cancer. We also investigated the function of P-Rex1 in melanoblasts, as the molecular pathways that drive their developmental migration are believed to underpin the movement of metastatic melanoma cells. Methods: P-Rex1−/− mice were crossed to mice carrying the DCT-lacZ transgene, a melanoblast reporter line, and a Tyr::NrasQ61K/°; INK4a−/− metastatic melanoma mouse model. Allograft tail vein (TV) injections were performed to further assess the endogenous function of P-Rex1 in metastasis. Panels of human melanoma cell lines and tissue were investigated with microarray, tissue culture, and immunohistochemical techniques. Results: P-Rex1−/− mice have a melanoblast migration defect during development (p=0.01), evidenced by a white belly. They were resistant to metastasis when crossed to the Tyr::NrasQ61K/°; INK4a−/− murine model of melanoma (1/30 mice with metastases vs 13/30 in control cohort; p=0.001). When melanocytes derived from this model were TV-injected into immune-competent allografts, endogenous P-Rex1 was found to facilitate metastatic incidence, growth, and organ spread following the intravasation stage of the metastatic cascade (p=0.02). Mechanistically, this was associated with P-Rex1 driving invasion in a Rac-dependent manner. In humans, P-Rex1 was elevated in the great majority of melanoma cell lines, with mRNA levels above the median statistically associated with metastasic propensity (p=0.005). Tissue immunohistochemistry revealed an association between tumor progression and P-Rex1 expression. Conclusions: P-Rex1 is a key component of melanoma progression, invasion and metastatic signaling, supporting the value of pharmacological inhibition of P-Rex1 activation of Rac for treatment of metastatic or high risk primary melanomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B147.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.004 |
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".