Abstract 1984: Activated BMP signalling modulates multicellular spheroid formation and reattachment of ascites-derived human epithelial ovarian cancer cells in an in vitro model of metastasis
Bibliographic record
Abstract
Abstract Epithelial ovarian cancer (EOC) comprises close to 90% of ovarian tumours, and over 75% of cases are not discovered until advanced metastatic stages. Therefore, there remains a critical need to identify the mechanisms controlling late-stage spread of disease and develop more effective treatment regimes. EOC cells have the ability to form multicellular aggregates in malignant ascites which dramatically alters cell signalling, survival, and metastatic potential. Primary human EOC cells derived from patient ascites secrete and are responsive to bone morphogenetic proteins (e.g. BMP2 and BMP4). BMPs can function in an autocrine fashion to enhance the malignant characteristics displayed by EOC cells in adherent monolayer culture. Herein, we demonstrate that EOC cells with enhanced BMP signalling form smaller, more loosely-aggregated spheroids than control cells when grown in suspension culture. Upon reattachment to standard tissue culture plastic, EOC spheroids readily attach and cells disperse from the attached spheroid; EOC spheroids with enhanced BMP signalling have an increased cell dispersion rate when compared with controls. Activated BMP signalling in EOC spheroids induces Smad1/5/8 phosphorylation, increases ID1 and ID3 proto-oncogene expression, and promotes epithelial-mesenchymal transition as evidenced by increased Snail and Slug and reduced E-cadherin markers. To identify additional target genes mediating the phenotypic changes in EOC spheroids due to activated BMP signalling, we performed genome-wide expression analyses using Affymetrix arrays. From this study, 102 genes were significantly upregulated and 52 downregulated in primary human EOC cells and spheroids with enhanced BMP signalling. A number of these genes have been previously identified as BMP targets or members of the BMP signalling pathway, several of which are involved in negative feedback regulation (e.g. noggin, Smad6 and Smad7), as well as several genes encoding proteins associated with cellular adhesion. In addition, using the online Connectivity Map resource (www.broadinstitute.org/cmap), we revealed that the PI3K-Akt-mTOR pathway may be impacted by an activated BMP pathway in EOC cells. Indeed, BMP signalling induces phosphorylation of Akt in both adherent primary human EOC cells and multicellular spheroids. Thus, we are currently investigating whether the PI3K-Akt pathway and the targets identified by microarray analysis are required for the BMP signalling effects on EOC spheroid formation and reattachment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1984. doi:10.1158/1538-7445.AM2011-1984
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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) | 0.001 | 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".