Abstract 4971: Splicing factor kinase regulates metastatic dissemination of human prostate cancer
Bibliographic record
Abstract
Abstract Metastasis causes the vast majority of cancer-associated deaths. Despite its clinical significance, the molecular mechanisms that regulate this multi-step process are poorly understood. To successfully disseminate a cancer cell must escape the primary tumor, travel to a distant site, arrest, enter the stroma and grow in a new microenvironment. The presence of circulating tumor cells in patients with metastatic disease and experimental animals with metastatic cancers suggests that tumor invasion is a critical, rate-limiting step in the metastatic process. To identify the key molecular determinants that regulate invasive metastatic lesion formation we performed the first whole-genome, in vivo RNAi screen in an avian embryo model using advanced intravital imaging techniques. We identified numerous novel regulators of cancer cell invasion, including JL1, a splicing factor kinase. In secondary assays, we demonstrated that JL1-depletion inhibits migration of several human cancer cell lines with no effect on proliferation or survival. Furthermore, JL1-deficient human cancer cells display diminished metastatic potential in chicken embryo and mouse models of metastasis. Cancer microarray database mining shows that JL1 gene expression is strongly associated with indicators of poor clinical outcome in prostate cancer, including pathological Gleason score and metastasis. To experimentally determine JL1 association with advanced disease we performed histological examinations of prostate cancer tissue and determined that JL1 staining strongly correlates with prostate cancer progression. JL1 kinase regulates alternative splicing of numerous cellular transcripts in response to stress and growth signals. To examine the molecular mechanism behind JL1 regulation of cancer cell metastasis, we performed exon level microarray analysis on JL1-depleted cancer cell lines. Subsequent interactome analysis identified an enrichment of key regulatory proteins in pro-metastatic networks. Therefore, we hypothesize that abrogated JL1 activity directly promotes prostate cancer cell migration and invasion. In summary, JL1 is a novel regulator of cancer cell metastasis that represents a potential pathological marker for prostate cancer progression, and novel drug target to block invasion and metastasis. Citation Format: David J. Bond, Konstantin Stoletov, Hon Sing Leong, Emma Woolner, Shuhong Liu, Tarek Bismar, Andries Zijlstra, John D. Lewis. Splicing factor kinase regulates metastatic dissemination of human prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4971. doi:10.1158/1538-7445.AM2014-4971
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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 | 0.001 |
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".